HANDBOOK GRADUATE STUDIES DEPARTMENT OF PHARMACOLOGY GRADUATE SCHOOL OF BIOMEDICAL SCIENCES THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER

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1 HANDBOOK OF GRADUATE STUDIES DEPARTMENT OF PHARMACOLOGY GRADUATE SCHOOL OF BIOMEDICAL SCIENCES THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO, TEXAS Revised August, 2007 Distribution - First Year Graduate Students, COGS, and New Faculty

2 TABLE OF CONTENTS TITLE PAGE Program Overview 4 Academic Standards 5 Coursework and Lab Rotations 5-6 Required Courses Exemptions Typical Course Schedule 6-7 Lab Rotations 8-10 Registration 10 The Ph.D. Qualifying Exam Admission to Candidacy 18 Dissertation Selection of Supervising Professor Selection of the Temporary Supervising Committee Preparation of Dissertation Proposal Procedures Temporary Supervising Committee & COGS Supervision of Dissertation Research Dissertation Supervisory Committee Meetings Registration for Dissertation Final Credit Hours Preparation of the Dissertation Chapter Format Traditional Format Final Oral Examination Granting of the Degree 24 Procedures for Dissertation and Thesis Binding Typing and Binding of Dissertation Paying for Binding and Microfilming Distribution of Copies for Binding 2

3 Master of Science in Pharmacology MS Thesis Requirements Miscellaneous Information Graduate Teaching/Research Assistantship Stipends Time to Degree Faculty Mentor Student Travel Copying Distribution of COGS Minutes Payment for Tutorial Services Proctoring of Examinations Tuition Health Insurance Course Descriptions Required Courses Elective Courses The Faculty and Their Research Interests APPENDIX Lab Rotation Evaluation Form A-1 Seminar Speaker Critique Form A-2 Petition for Oral Examination for Advancement to Ph.D. Candidacy A-3 Petition for Admission to Candidacy (GSBS 32) A-4 Temporary Dissertation Supervisory Committee Form A-5 Dept. of Pharmacology Approval of Research A-6 Recommendation for Approval of Research Proposal & Supervising Committee (GSBS 30) A-7 Dissertation Supervising Committee Report A-8 Request for Final Defense & Oral Examination (GSBS 40) A-9 Report on Final Oral Examination (GSBS 43) A-10 3

4 PROGRAM OVERVIEW The graduate program leading to the Ph.D. degree in Pharmacology is designed to provide the strong background in research methodology and experimental design necessary for a professional career in academia, industry or governmental service. Generally five years are required to complete the requirements for the Ph.D. Students are expected to complete the required course work and complete the qualifying examination for the Ph.D. by the Summer session of their second year. Following successful completion of all required courses and the qualifying examination and satisfactory research progress, students are admitted to candidacy for the Ph.D. During the third year, students are expected to develop a dissertation research proposal and present it at a departmental seminar. Students are encouraged to present at a departmental seminar each year and to make presentations of their research data at national scientific meetings. Disclaimer The provisions of this Handbook do not constitute a contract, expressed or implied, between any applicant, student, or faculty member and the Department of Pharmacology, the Graduate School of Biomedical Sciences, The University of Texas Health Science Center at San Antonio, or The University of Texas System. The Department of Pharmacology reserves the right to alter course offerings at any time or to change the curriculum or any other procedures leading to the awarding of a degree and any other requirements affecting students. Changes will become effective whenever the proper authorities so determine. The changes will apply to prospective students and may apply to those already enrolled. Revisions Recommendations for improving the content of this handbook are welcomed from the students and any members of the faculty of the Department of Pharmacology. Abbreviations and Definitions Used in this Publication Dean UTHSCSA GSBS GFC COGS Faculty Dean of the Graduate School of Biomedical Sciences The University of Texas Health Science Center at San Antonio Graduate School of Biomedical Sciences Graduate Faculty Council Committee on Graduate Studies of the Department of Pharmacology Unless noted otherwise, Graduate Faculty of the Department of Pharmacology 4

5 ACADEMIC STANDARDS Students majoring in pharmacology are expected to maintain a Satisfactory (S) grade in Seminar, Research, Dissertation, Supervised Teaching and Special Topics and at least a letter grade of B in all of their graduate courses. GSBS guidelines state that a student must maintain a cumulative GPA of 3.0. A student, whose cumulative GPA falls below 3.0, is automatically placed on probation by the Dean and warned that continuation in the graduate program is in jeopardy. While on probation, the student must maintain a B average in all subsequent semesters for which he or she is registered. Failure to achieve a 3.0 in the course work for any semester could result in the student being considered for dismissal from the Graduate School by the COGS and/or the Dean. A student will remain on probation as long as the cumulative GPA remains below 3.0. A student may not withdraw from any courses while on academic probation. If a letter grade of C or U is received in any pharmacology course, the student will be referred to COGS for consideration. Generally, the student will be required to repeat the course. A letter grade of C in two or more graduate courses or a letter grade of D in any graduate course could result in COGS recommending that the student be dismissed from the graduate program. COGS will decide on the appropriate course of action following a review of each case. Appeal Process A student may appeal to COGS to reconsider any policy decision that may affect the student's progress or tenure in the Pharmacology Graduate Program. In those cases where dismissal is recommended to the Dean, the student may appeal to COGS to reconsider its recommendation for dismissal. If COGS still recommends dismissal from the graduate program, then the student may appeal to GFC to reconsider the recommendation. COURSE WORK AND LABORATORY ROTATIONS Required Courses All students enrolled in the Ph.D. program in Pharmacology are required to take the following courses: CSBL 5095 INTD 5000 INTD 6002 PHAR 5001 PHAR 5013 Experimental Design and Data Analysis (Statistics) Fundamentals of Biomedical Sciences Ethics Pharmacology Principles of Pharmacology 5

6 PHAR 5020 PHAR 5090 PHAR 5092 PHAR 6071 PHAR 6097 PHAR 7099 PHAR Basics of Research Design Pharmacology Seminar Special Problems in Pharmacology/Laboratory Rotations (two semesters required) Supervised Teaching in Pharmacology Research Dissertation (2 semesters required) 4 credits of Electives (minimum) Exemptions An exemption from any of the courses listed above may be requested if the student has taken similar courses and received at least a letter grade of B. The student should petition COGS as soon as possible after admission to the graduate program for exemption from a given course. TYPICAL COURSE SCHEDULE FOR THE FIRST TWO YEARS Fall Semester First Year Course Number Course Title Credit Hours INTD 5000 Fundamentals of Biomedical Sciences 10.0 TOTAL 10.0 Spring Semester First Year Course Number Course Title Credit Hours PHAR 5001 Pharmacology 4.0 PHAR 5013 Principles of Pharmacology 3.0 PHAR 5090 Pharmacology Seminar 1.0 PHAR 5092 Special Problems: Laboratory Rotation 1.0 TOTAL 9.0 6

7 Summer Semester First Year Course Number Course Title Credit Hours PHAR 5020 Basics of Research Design 1.5 PHAR 5092 Special Problems: Laboratory Rotation 1.0 PHAR 6097 Research 3.5 Fall Semester Second Year TOTAL 6.0 Course Number Course Title Credit Hours CSBL 5095 Experimental Design and Data Analysis 2.0 PHAR 5090 Pharmacology Seminar 1.0 PHAR 6097 Research --- PHAR * Electives --- TOTAL 9.0 Spring Semester Second Year Course Number Course Title Credit Hours INTD 6002 Ethics in Scientific Research 0.5 PHAR 5090 Pharmacology Seminar 1.0 PHAR 6097 Research --- PHAR * Electives --- QUALIFYING EXAM (see pages for details) TOTAL 9.0 *A total of 4 credit hours of Electives/Micro-electives are required. These credits should be obtained by the end of the second year. Summer Semester Second Year Course Number Course Title Credit Hours PHAR 6097 Research 6.0 TOTAL 6.0 7

8 LABORATORY ROTATIONS Students must complete two laboratory rotations in different laboratories by the end of their first year in the graduate program. Each rotation is a full-semester rotation and students are required to write a report and to present a 15-minute post-rotation talk following the completion of each laboratory rotation. Students are encouraged to work with their Lab Rotation supervisor who will assist them in the preparation and organization of the oral presentation. At the beginning of the rotation, the Lab Rotation supervisor will discuss the criteria (below) that will be used to evaluate the performance of the student during the laboratory rotation. The Graduate Program Coordinator will provide a written copy to all students at the beginning of the rotation. Entering students have the option of beginning their graduate training early by undertaking a rotation in the summer semester prior to the first year of classes. Students are expected to spend at least 12 hours per week in their laboratory rotations during the fall and spring semester rotations and work full-time during the Summer semester rotation. The project should be terminated at least one week prior to the end of the semester to give the student time to prepare the written report on the project and present their post-rotation talk. Completion of the rotation may not be extended into the next semester, including the completion of the written report. At the end of the rotation, students write a short report (about 10 double-spaced, typewritten pages) in journal style (i.e. Introduction, Methods, Results and Discussion). One copy of the report is given to the Lab Rotation supervisor for evaluation and grading (see below), and a second copy is given to the Graduate Academic Coordinator to serve as a file copy. Lab rotation supervisors must be selected from the Graduate Faculty of the Pharmacology Graduate Program who have active research laboratories. Special Problems Project Criteria a. The Objective The objective of the lab rotation is two-fold: 1. To give students an opportunity to develop research skills and aid them in selecting a laboratory in which to pursue their dissertation research. 2. To permit faculty to evaluate the laboratory skills and potential research aptitude of the student. 8

9 b. The Project The design of rotation projects is the responsibility of the mentor and should be done prior to accepting a student in the laboratory. The research project need not be an original research investigation. It can be an extension of some experiment that is performed routinely in the mentor s laboratory or some methodology that is feasible for a student to complete in the allotted time. It is critical that the mentor supervising the project develop a concise and well-defined project for the student. The project should satisfy the following criteria: 1. The project should be hypothesis-driven. 2. The methodology required to complete the project should currently be in use in the laboratory. 3. There should be a reasonable expectation of some success within the allotted time. c. The Evaluation The student will be evaluated on the following criteria: 1. Technical competence 2. Motivation 3. Understanding of the techniques and instrumentation used in the rotation. 4. Understanding of scientific concepts and principles pertinent to the project. 5. Ability to read and critically evaluate literature. 6. Ability to work, think and write independently. The mentor should meet regularly with the student to discuss the student s performance based on the above criteria. At the end of the rotation period, a rotation evaluation form (page A-1) will be sent to the mentor. The mentor will give the student an A (excellent), B (average) or C (unsatisfactory) grade for each criterion. The mentor must meet with the student to discuss the evaluation and have the student sign the evaluation form to indicate that he/she has had the opportunity to review and discuss the evaluation with the mentor. The evaluation is then submitted to the Chair of COGS. These evaluations are then placed in the student's file and are available for review by the faculty. d. The Written Report The report is to be given to the mentor before the end of the semester. The written report is to follow the format of a short research communication (about 10, doublespaced, typewritten pages) consisting of the following parts: 1. Introduction 2. Methods 3. Experimental Results 4. Discussion 9

10 5. Summary and Conclusions 6. References (no more than references) Each student should prepare two copies of the written report; one copy is to be given to the Graduate Program Coordinator to be kept as a file copy and the other copy is to be graded by the supervising faculty member. e. The Post-Rotation Talk: Students are required to give a brief (approximately 15 minutes) post-rotation talk to the Department on the research project that should state the hypothesis tested, cite specific objectives, give a brief discussion of the methodology employed and summarize the results obtained in the study. Among those in attendance, members of the Department will be asked to complete Seminar Speaker Critique forms (page A-2) to provide constructive criticism to the speakers. In addition, the presentations will be video-taped. The video tape will be provided to the student for his/her own viewing. It is suggested that the student review the tape and discuss the critique forms with his/her mentor. f. The Grade: Students receive a letter grade for each semester of Special Problems that is based equally upon the evaluation of the student's performance in the laboratory (50%) and on the written report (50%). REGISTRATION The Registrar s Office will notify students via of the dates open for web-based registration. Prior to registering, students should obtain any necessary permit numbers from the Graduate Academic Coordinator. To be enrolled as a full-time student for the Fall and Spring semesters, students must register for a minimum of 9 credit hours; for the Summer semester, students must register for a minimum of 6 credit hours. At the time of registration for each semester, students should also submit a UTHSCSA Health Insurance Coverage Information form to the Registrar s Office to show proof of health insurance coverage. Registering for Final Credit Hours A student may register for final credit hours during the semester or summer session s/he plans on defending her/his dissertation. A student registering for final hours is exempt from the minimum tuition requirement and only required to pay tuition for 3 credit hours. 10

11 THE PH.D. QUALIFYING EXAMINATION Passing the qualifying examination is one of the steps required for advancement to candidacy. The other steps are satisfactory completion of all required courses (average GPA of at least 3.0) and certification by the supervising professor that the student has demonstrated the potential for productive and independent investigation. The examination includes both a written and an oral component. Objective The overall objective of the examination is to determine whether the student has a sufficient basis of knowledge, a command of the scientific method, and originality of thought necessary for advancement to the subsequent phase of mentored, thesis work as a Ph.D. candidate. Specific objectives include assessment of the capacity of a student to: 1) assemble a database of knowledge on a particular topic; 2) use that database of knowledge to develop a focused and original research question and to propose specific testable hypotheses; 3) use the scientific method to design experiments to test the proposed hypotheses; 4) propose methods to evaluate the anticipated results of the experiments and consider alternative approaches; and 5) to communicate both orally and in writing. Responsibilities of the Faculty Advisor A student is encouraged to request that a member of the Pharmacology graduate faculty serve as an advisor during the preparation for the examination. The faculty advisor will attend the oral examination as a non-participating, non-voting observer. The role of the faculty advisor will be to serve as a consultant to provide the student with general guidance in preparation of the proposal. The faculty advisor should advise the student whether the proposal is generally ready for distribution (i.e., thorough, well researched, generally accurate, etc.). The faculty advisor will not play an active role in the formulation of the research proposal and should not suggest specific goals, experiments, methods or analyses. The responsibility for the quality of the proposal in terms of originality, approach to solving the problem or testing the hypotheses, and significance rests completely with the student. The student may give an original interpretation or a re-interpretation of literature data, propose a series of experiments to test a hypothesis, or present a new theoretical approach to a problem. The Examination Committee The examination committee will comprise four graduate faculty members from the Department of Pharmacology and one graduate faculty member from another department at UTHSCSA. The examination committee will be chosen by the COGS who will select one of the four Department members to serve as chairperson. 11

12 Responsibilities of the Examination Committee Determine the initial feasibility of the proposal based on the student s outline Determine if the written proposal provides an adequate basis for an oral examination Provide the student with written comments/recommendations (in the event that the initial written proposal is not deemed suitable for defense) Sign the Petition for Oral Examination upon approval of the written proposal Conduct the oral examination Determine whether or not the student has satisfactorily defended his/her written proposal Sign the Petition for Admission to Candidacy or, in the event that the defense has been deemed unsatisfactory, provide the student with feedback that outlines specific aspects of the student s performance that need improvement in a second examination. Responsibilities of the student Discuss ideas about a proposal with a faculty advisor Write and submit to the examination committee an outline of a proposal Write and submit to the examination committee an original proposal Present a copy of the proposal with a signed Petition for Oral Examination form to the COGS chair when the committee has approved the proposal Inform the COGS chair of the date of the oral examination Defend the proposal to the examination committee in an oral examination Consult with the faculty advisor regarding the commitment of time and insure that all other research and academic responsibilities are met Scheduling Except under special circumstance, approved by the COGS, the examination must be completed by 30 June in the summer following the second academic year. If a student enters the program in January, the deadline will be extended to 28 February in the second academic year. The student is responsible for scheduling all activities related to the examination. Suggested Timeline Choose a faculty advisor and discuss possible topics in January (2nd year) Submit outline by 1 February Prepare written proposal during February and March Submit final proposal by 1 April Complete oral examination by 1 June Should a retest be necessary, both components of the examination (written and oral) must be completed by 30 June. If a student fails to successfully complete the qualifying examination by this deadline, his/her progress will be reviewed by COGS with the possibility of suspension of stipend or dismissal from the program. 12

13 General Guidelines for the Preparation of the Written Proposal to be used as the Basis of the Oral Examination a) The written component will comprise an NIH NRSA-style research proposal written on any acceptable topic related to pharmacology. It is permissible for the student to choose a topic in the area in which he/she plans to do his/her dissertation studies. b) The proposal must include hypothesis-guided experiments. The experiments should be designed to produce results, which clearly support or reject the associated hypotheses. It is not acceptable to propose experiments that are likely to yield equivocal results that will not discriminate between the truth or fallacy of the hypothesis. It is not acceptable to list a hypothesis that one cannot imagine to be false. It is not acceptable to propose purely descriptive experiments (i.e., I'll do this and see what happens.). c) The proposal should describe a project that one person could execute in about two years of work. d) The experiments proposed should be the logical next steps in some area, or should reinforce and extend recent advances in the area. Format of the Written Proposal a) The text can not exceed 10 single-spaced typed pages, including figures and tables. Figures should have a title and a legend. Tables should have a title and an explanatory footnote. Figures and tables should be numbered as referenced in the text. Include attribution in the legend if a figure has been copied from elsewhere. Hand-drawn diagrams are acceptable so long as they reproduce legibly. Figures may be annotated to make your point more clear. Preliminary results are not expected. The proposal should have a cover page with a title and names of the student, faculty advisor, and examination committee members. A suggested breakdown for the text is as follows: Abstract: ½ page Specific Aims with Hypotheses: 1 page Background & Significance: 2-4 pages Experimental Design & Methods: 2-4 pages Literature Cited: Not included in the 10-page limit b) Observe NRSA Guidelines: At least 0.5 inch margins on all sides Number and place name on all pages At least 10 point font (Helvetica or Arial 12 point is suggested) Type density, including characters and spaces, can not exceed 15 characters per inch References are unlimited and should be cited from the text by author and year 13

14 c) The proposal must not contain text that is extensively quoted or paraphrased from any other work. Any quoted material must be given proper attribution. Content of Specific Sections a) Abstract The abstract should provide an overview of the entire project including: 1) Background; 2) Hypotheses; 3) Aims; 4) Experimental Approaches and 5) Significance. b) Specific Aims Each (usually 2-4) should be summarized in a single numbered, explicit sentence associated with a short explanatory paragraph. At least one aim should be in the form: Aim X is to test [hypothesis] by [experimental strategy]. Multiple aims could test the same hypothesis by different approaches, or test different hypotheses with the same collection of data. Some aims may be preparatory (i.e., to prepare a mutant protein, or to establish the power of a method on some test material, or to clone a gene); however, some of the aims must purpose studies that will test specific hypotheses. c) Background and Significance Briefly discuss the background to the proposal, critically evaluate current knowledge, and specifically identify voids in the literature that the project will address. State concisely the importance of the research to longer-term objectives. An exhaustive survey of the literature and a lengthy bibliography are not required as part of the written proposal, although the student will be expected to demonstrate a thorough understanding of the relevant literature during the oral defense. In the written document, include only information that defines the problem and that justifies the proposed work. d) Experimental Design and Methods Discuss the experimental design and the procedures to be used to accomplish the specific aims. Include the means by which the data will be analyzed and interpreted. Describe any new methodology and its advantage over existing methodologies. Discuss the potential difficulties and limitations of the proposed procedures and provide alternative approaches to achieve the aims. The Experimental Design includes topics such as how many samples will be needed, what controls will be needed, and exactly what measurements will be the basis of determining whether or not the hypotheses are supported (accepted or rejected). Experimental Design often is best organized according to the aims. The Methods include precisely how an experiment is to be carried out. Methods may be included within the Experimental Design section; however, since the same methods are often used in several aims, it is sometimes more convenient to provide Methods in a separate section. Do not include an exhaustive list of details for Methods; rather give the name and purpose of the method, the reference you would follow and a brief discussion of how you will address any potential weaknesses in the methods. Do not invent new methods unless that is 14

15 an explicit aim of the proposal. During the oral examination, the student will be expected to demonstrate a knowledge of the theory behind the methods. This section often includes brief descriptions or discussions of the following: 1) future directions; 2) possible outcomes and potential problems and 3) expected timeline. e) Literature Cited For each citation, provide the names of all authors, the article title, the name of the book or journal, volume number, page numbers, and year of publication. Arrange in alphabetical order by first author. If you cite a reference, you are expected to have read and understood it. The committee may request inclusion of a recent Medline, or the equivalent, literature search in addition to the cited literature. Oral Defense During the oral component of the examination, the committee members examine the student on the proposal and related areas of pharmacology. The oral component will consist of a brief (15-minute) formal presentation (e.g., PowerPoint) by the student that summarizes each of the elements of the proposal, followed by questions from and discussion with the examination committee. Grading Grading of the qualifying examination will be pass/fail and will be determined by the examination committee based on the student s performance on two components of the examination. At least four of the five members of the examination committee must vote each component as pass for the student to successfully complete the examination. Specific Issues to be Assessed During Grading Does the student possess sufficient knowledge in the area of the examination? (Note: In the absence of remembering details, a perspective on what is known, where it might be found and how it might be applied usefully to the problem should be considered favorably as a basis of knowledge.) Has the student demonstrated an understanding of fundamental pharmacological principles? Has the student researched the specific background of the proposal well enough to understand the overall theory governing the work in this area? Can the student state how unexpected results would affect the current theory? Does the student have an understanding of the theory underlying the specific methods proposed? Can the student distinguish a hypothesis from a belief (a statement that the student cannot imagine being wrong)? 15

16 Can the student recognize when an experiment clearly rejects or supports a hypothesis? Does the student appreciate the implications of negative data? Can the student identify and provide potential solutions for weaknesses in the proposal? Does the student provide appropriate controls to address possible weaknesses? Can the student discuss what future direction should be taken given some specified outcome of the proposed experiments? Specific Recommended Chronology of events Except under special circumstance, approved by the COGS, the examination must be completed by 30 June in the summer term following the second year. If a student enters the program in January, the deadline will be extended to 28 February. The examination will be considered failed if not completed by the deadline. Since several revisions of the proposal may be required, students are strongly encouraged to begin several months before the deadline. 1) The student chooses a general topic for the proposal, requests a member of the Pharmacology graduate faculty to serve as an advisor, and discusses the proposal topic with the faculty advisor in terms of general feasibility. 2) The student writes an outline of the proposal (maximum of two pages) and submits it to the chair of COGS who will convene a meeting of COGS to choose members of an examination committee and a committee chairperson. Each of the members of the examination committee will be given the outline. 3) Three days after distribution of the outline, the chairperson of the examination committee will solicit opinions from the other committee members concerning the feasibility of the proposed qualifying examination subject. The chairperson then consults with the student about the committee s evaluation and either advises the student to write the full proposal (see below) or advises the student that the topic or specific aims do not form an adequate basis for a proposal. In the latter case, the student may re-write or submit a different outline for consideration. The preparation of an acceptable proposal is the responsibility of the student. 4) Upon being advised to continue, the student writes the full proposal taking into consideration any initial concerns/suggestions of the committee. 5) The student distributes the full proposal to the committee. After two weeks, the committee members consult with the chairperson of the committee as to whether or not the proposal is approved for oral defense. If the proposal is not approved, the student will receive from the chairperson of the examination committee written comments from each of the examination committee members. The student then may re-write the proposal on a new topic or modify the original proposal based on the comments and recommendations of the committee. Upon resubmission of the written component, the student will 16

17 be advised that they have either 1) passed the written component, at which point they will schedule the oral component of the examination or 2) failed the written component a second time, at which point they will be removed from consideration for advancement to candidacy. A proposal may be defensible (i.e. that it is based on testable hypotheses), but still be deficient (e.g. in experimental design or in scientific writing) such that a re-write is required. The student, not the committee, is responsible for generating an acceptable proposal. If serious flaws persist in the re-written proposal, the committee may approve the proposal for the oral exam and then question the student on the deficiencies of the proposal in the oral exam. Thus, approval of the written proposal does not guarantee that its content will be sufficient to pass the exam. When the committee members approve the written proposal, they sign the Petition for Oral Examination form (page A-3). The student forwards the signed form and a copy of the proposal to the COGS chair. At this time, the student schedules the oral exam, which should be completed by 1 June in the summer following the second year. The committee is entitled to a two-week period between approval of the written proposal and the oral examination. The student may consult with committee members about material to be covered in the examination. 6) During the oral component of the examination, the committee members examine the student on the proposal and related areas of pharmacology. The committee will question the student until a consensus is reached that ample information is available on which to evaluate the student s performance. A maximum of three hours will be allotted for the examination. 7) Approval of four of the five committee members is required for the student to pass the qualifying examination. Upon approval, examination committee members sign GSBS Form 32: Petition for Admission to Candidacy (page A- 4) to substantiate that the student has passed the qualifying examination. The student will be allowed to repeat the oral examination with the same committee one time if the student fails. The chairperson of the committee shall confer with the committee, the COGS chair, and faculty advisor to construct the requirements for the re-examination. They should agree on a format for a re-examination designed to allow the student to correct deficiencies revealed during the initial examination. The format may be a written follow-up with no oral examination, a repeat of the oral exam with no further writing, or both a re-write and a repeat oral examination. Within one week, the chairperson of the committee will give the student and the COGS chair a written explanation for the basis of the failure and provide guidelines to prepare for the re-examination. The re-examination must be completed within three months of the first examination and by the 30 June deadline. If the student fails the re-examination, the student will be removed from consideration for advancement to candidacy. 17

18 8) Upon completion of the qualifying examination, satisfactory completion of all required courses, certification by the Supervising Professor that the student has clearly demonstrated the potential for productive and independent investigation, and receipt of GSBS Form 32 (page A-4), COGS will decide whether to recommend to the Associate Dean of the Graduate School that the student be admitted to candidacy for the Ph.D. degree. The Associate Dean makes the final decision on admission to candidacy for the Ph.D. degree. ADMISSION TO CANDIDACY Requirements for Admission to Candidacy 1. Satisfactory completion of all required courses. 2. A cumulative GPA of at least 3.0 in all course work undertaken since matriculation in the program. 3. A report by the chair of COGS that the student has passed the qualifying examination. 4. A report by the student's chosen dissertation supervisor that the student has clearly demonstrated the potential for productive and independent investigation. 5. If the overall evaluation of the eligibility of the student for admission to candidacy for the Ph.D. degree is favorable, then COGS votes on approval of admission of the student to candidacy. The chair of the COGS then submits a Petition for Admission to Candidacy for the degree of Doctor of Philosophy Form (page A-4) to the Dean for approval. 6. If approved, the student receives an official notification of admission to candidacy from the Dean of the Graduate School (GSBS Form 35). DISSERTATION Selection of the Supervising Professor Students are encouraged to select a member of the Pharmacology Graduate Faculty who will serve as the supervising professor for his/her dissertation research as early as possible after completing the required lab rotations. The student is required to petition the COGS in writing for approval of the proposed dissertation supervisor. The faculty member must have an active research lab, be willing to serve as the student s dissertation supervisor and must have funds to support the student s stipend and research activities for the entire time required to complete the dissertation research 18

19 project (usually 3 years). COGS will not approve a faculty member as a dissertation supervisor who does not have funds to support the student s research and stipend. Selection of the Temporary Supervising Committee A Temporary Supervising Committee should be formed to assist the student in preparing the dissertation research proposal. This committee should be formed as soon as possible after the student has chosen a mentor, but no later than three months after the student s Admission to Candidacy. The members of this committee are selected according to the mutual agreement of the student, the supervising professor and the prospective committee members. The supervising professor must submit to COGS the Department of Pharmacology Temporary Dissertation Supervising Committee Form (page A-5) that lists the members of this committee. COGS will vote to approve the committee or make recommendations for changes in the committee to the supervising professor. In most instances, members of the Temporary Supervising Committee become members of the permanent supervising committee. The temporary supervising committee must consist of at least four members: 1. the supervising professor, who serves as the chair of the supervising committee. 2. two additional members from the Graduate Faculty of the Pharmacology Graduate Program. 3. one member who must be a faculty member at UTHSCSA but not a member of the Pharmacology Graduate Program. Preparation of the Dissertation Proposal During the first year following admission to candidacy, the student should prepare his/her dissertation proposal in the format of a National Research Service Award (NRSA) grant proposal and submit the proposal to the Temporary Dissertation Supervising Committee for approval. The format for an NRSA is presented below. Additional information on NRSAs can be obtained from the NIH s website ( Students should include sufficient information in their proposal to permit an effective review without reviewers needing to refer to the literature. Brevity and clarity in the presentation are considered indicative of a student s approach and ability to conduct a superior project. The entire proposal is not to exceed 10 pages including all tables and figures. The format for the proposal is as follows: 1. Specific Aims - State the specific purposes of the research proposal and the hypotheses to be tested. 19

20 2. Background and Significance - Sketch briefly the background to the proposal. State concisely the importance of the research described in this application by relating the specific aims to broad, long-term objectives. 3. Research Design and Methods - Provide an outline of: o o o Research design and the procedures to be used to accomplish the specific aims; Tentative sequence for the investigation; Statistical procedures by which the data will be analyzed 4. Potential experimental difficulties should be discussed along with alternative approaches that could achieve the desired aims. Once the committee approves the proposal, the student will present the proposal to the Pharmacology Faculty as a departmental seminar and defend the proposal in a COGS meeting following the seminar presentation. The COGS must approve each student s dissertation proposal and Permanent Supervising Committee. Procedures - Temporary Supervising Committee The Temporary Supervising Committee must first approve the dissertation research proposal and sign the Department of Pharmacology Approval of Research Proposal Form (page A-6). The student submits this form to the Graduate Program Coordinator. The student schedules a seminar at which s/he presents the dissertation research proposal to the Pharmacology Faculty. The student gives a copy of the approved written dissertation proposal to the Graduate Program Coordinator to distribute to each member of COGS at least one week in advance of the presentation of the dissertation research proposal at a departmental seminar. Procedures - COGS The student defends her/his dissertation research proposal to COGS at a meeting of COGS after her/his dissertation proposal seminar. During the defense, the supervising professor is present as a quiescent observer. Following the defense, the student is excused from the room and the supervising professor has the opportunity to share comments about the proposal made by the Temporary Supervising Committee. Following discussion and approval of the dissertation research proposal by the COGS, 20

21 the Supervising Professor presents and describes the qualifications of the proposed membership of the permanent committee. The Permanent Supervising Committee must consist of at least five members. The Supervising Professor serves as the chair of the supervising committee. Four of the members must be from UTHSCSA (the supervising professor, 2 members from the Pharmacology graduate faculty and one other UTHSCSA). One member must be from an outside institution not affiliated with UTHSCSA. It is the responsibility of the supervising professor to contact the proposed external committee member to determine if the individual is willing to serve on the student's dissertation supervising committee. The supervising professor should provide the individual with a copy of the dissertation research proposal to review and request that s/he provide comments about the strengths and weaknesses of the proposal. Additional members may be added as deemed appropriate. COGS votes on whether or not to approve the proposed membership of the Permanent Supervising Committee. The Chair of COGS prepares and sends the Recommendation for Approval of Dissertation Research Proposal and Supervising Committee Form (page A-7) to the Dean signifying that COGS has reviewed and approved the dissertation research proposal and the Permanent Supervising Committee. SUPERVISION OF THE DISSERTATION RESEARCH Dissertation Supervisory Committee Meetings The Dissertation Supervisory Committee (temporary or approved) is required by COGS to meet by the end of the term each fall and spring. The student will provide a written progress report to her/his committee prior to the meeting. The report should include what the student s research aims were during the semester, the results of her/his research and how the student plans to proceed during the next reporting period. The report should not exceed six pages. The supervising professor is required to provide the Chair of COGS with a brief written report of the student's research progress (page A-8). If the Chair of the COGS does not receive a report of the student s progress by the end of the semester, the student will not be allowed to register for the subsequent semester. The scheduling of these meetings is the student s responsibility. Major changes in the research status of the candidate, such as the selection of a new supervising professor, new Supervising Committee Members or a substantive change in research direction, must be submitted to COGS for approval. Registration for Dissertation Students on the Ph.D. degree track may register for the Dissertation course (PHAR 7099) after the following actions have been taken: 21

22 Approval of admission to candidacy for the Ph.D. degree by the Dean Approval of the dissertation research proposal by COGS and the Dean Approval of the membership of the candidate s Supervising Committee by COGS and the Dean A candidate for the Ph.D. degree must register for at least two terms of Dissertation credits. Only one of the terms may be a summer session. Final Credit Hours A student must be registered for the semester or summer term in which s/he graduates. If a student is registering for only final credit hours in preparation of a dissertation and registers for no other courses, s/he is exempt from the minimum tuition requirement and pays only tuition based upon the number of credit hours for which s/he registers. Such registration shall be considered a full-time course load. The minimum number of final credit hours for the Ph.D. degree is three. A student may register for final credit hours only once. International students must obtain approval from the Office of International Services (OIS) before registering for less than a full course load by completing and submitting a Request for Authorization to Reduce Course Load (available in OIS). PREPARATION OF THE DISSERTATION When the data collection is completed or close to completion, the student will request permission from the Supervising Committee to stop doing experiments and to begin writing the dissertation. Selection of Dissertation Format There are two formats that may be used for the Ph.D. dissertation: the Traditional Format and the Chapter Format. The Chapter Format is the default format for all Ph.D. dissertations. Students wishing to use the Traditional Format must receive the approval of both their supervising committee and of COGS. The Chapter Format consists of the following sections: a. Abstract b. Table of Contents c. General Introduction d. Literature Review e. Chapter I, II, III, etc. f. General Discussion g. Summary and Significance h. References 22

23 Each chapter should be organized in the format of an article that would be published in a scientific journal as follows: a. Title Page b. Abstract c. Introduction d. Materials and Methods e. Results f. Discussion The Traditional Format consists of the following sections a. Abstract b. Table of Contents c. General Introduction d. Literature Review (This may be combined with the Introduction.) e. Materials and Methods f. Results g. Discussion h. Summary i. Appendix j. Literature Cited A detailed description of the traditional format can be found in the booklet entitled "Instructions for Preparation & Submission of Theses, Dissertations and Dissertation Abstracts". The booklet can be downloaded from the GSBS website. FINAL ORAL EXAMINATION When the supervising committee judges the dissertation to be suitable for defense, the supervising professor shall submit a Request for Final Defense & Oral Examination Form (page A-9) signed by all committee members (except the outside member) to the Chair of COGS for her/his signature. The signed request form, together with 3 copies of the abstract and the student s curriculum vita, must be submitted to the office of the GSBS at least two weeks prior to the scheduled date of the final oral examination. In addition, one copy of the entire dissertation should be submitted to the GSBS for the formatting to be checked. The GSBS makes the public announcement of the final oral examination. However, it is the responsibility of the candidate and the supervising professor to inform the faculty and students of the Department of Pharmacology of the final oral examination. All interested persons may attend the public defense and have the right to question the candidate. After the public defense, the final oral examination continues with an oral examination by the supervising committee. The supervising committee conducts the final oral examination with the supervising professor serving as the chair. This portion 23

24 of the examination is restricted to the members of the student's supervising committee. The members of the supervising committee vote on the candidate's success or failure on the final oral examination. More than one vote for failure signifies failure of the examination. The supervising professor submits the Report on Final Oral Examination Form (page A- 10) to COGS for approval or disapproval of the recommendation by the supervising committee. In the event of a failing performance by the candidate, the supervising professor and supervising committee will submit a recommendation to COGS regarding remedial action. COGS shall decide on the recommendation or other action to be taken. GRANTING OF THE DEGREE If COGS approves the recommendation of the supervising committee, then the Chair of COGS signs and submits the Report on Final Oral Examination (page A-10) along with the final typed copy of the dissertation, including the Dissertation Approval Page signed by all of the supervising committee members, to the Dean. The Chair of COGS reviews the academic performance of the candidate as well as her/his performance on the final oral examination. The COGS Chair certifies that the candidate has satisfied all of the requirements for the degree of Doctor of Philosophy and recommends to the GFC that the candidate be granted the degree. If the GFC approves the recommendation, then the Dean will notify the President of the Health Science Center that the candidate has fulfilled all requirements of the GSBS for the Ph.D. Upon the candidate's certification by the President, the degree is conferred by the University of Texas System Board of Regents. If the GFC does not approve the recommendation, it will refer the matter to COGS with a recommendation for remedial action. PROCEDURES FOR DISSERTATION AND THESIS BINDING Typing and Binding of Dissertation Departmental staff will not type rough drafts or final copies of the dissertation or curriculum vita. Completion of these tasks is the responsibility of the student. The following copies of the dissertation are required: 2 copies for the Briscoe Library (1) original copy printed on 100% cotton bond paper with original photographs and (1) print shop copy 1 original copy printed on 100% cotton bond paper with original photographs for the student 24

25 1 print shop copy for the Pharmacology Departmental Library 1 print shop copy for each committee member including the outside member Paying for the Binding and Microfilming 100% cotton bond paper is provided by the Pharmacology Department. The Department will pay for up to 10 copies of each dissertation/thesis. A print shop requisition will need to be completed and the student will need to take the dissertation to the print shop for copying. The Briscoe Library pays for the binding of one original on 100% cotton bond paper. The Pharmacology Department will cover the costs of copying the dissertation/thesis. In addition, the Department will pay for the binding of up to 10 copies of the dissertation/thesis (one copy for the Departmental Library, one copy for the Briscoe Library, one copy for each committee member, and one copy for the student). The Pharmacology Department will also pay for the microfilming of the dissertation. Additional copies may be bound at the student s expense and the student must pay to have the dissertation sent off for binding via certified mail. The student should go to the Graduate Dean s Office (Rm. 414A) and get an Inter- Departmental Transfer Voucher listing all of the dissertation copies that the Pharmacology Department will pay for binding and microfilming. The Inter- Departmental Transfer Voucher is then taken to the Graduate Program Coordinator for her/his signature and then the form is returned to the Dean s Office. Distribution of the Copies for Binding After the binding and microfilming fees have been paid, the student delivers the copy to be microfilmed to the Graduate Dean s Office. Each copy should be placed in a separate, labeled envelope (i.e. Tom Smith / Briscoe Library) and delivered to the binding section of the library located on the second floor across from the computer laboratory. 25

26 MASTER OF SCIENCE IN PHARMACOLOGY The Department of Pharmacology does not offer a Master of Science degree in Pharmacology. However, under special conditions, a student may petition to change academic tracks from Ph.D. to M.S. The student must submit to the Chair of COGS a formal request explaining why it is necessary for her/him to change academic tracks. If the request is approved by COGS, the student s petition is then forwarded to the Graduate Dean s office for approval. The MS degree is granted upon satisfactory completion of a minimum of 30 semester hours, additional requirements as determined by COGS, recommendation of the GFC and certification of the candidate by the Dean and President to the Board of Regents. Master of Science Thesis Requirements Thesis Supervising Professor After the student s change of academic program is approved, the student must choose a supervising professor for her/his thesis research. The student should petition COGS in writing for approval of his/her thesis supervisor. The faculty member must be a member of the Pharmacology graduate faculty, have an active research program, be willing to serve as the student s thesis supervisor and must have funds to support the student for the entire time required to complete the thesis research project. A student may not select a faculty member who does not have research funds to provide stipend support for the student. Draft of the Thesis Research Proposal The candidate shall submit a draft of a proposal for the thesis research to the supervising professor for review and modification. Subsequent drafts of the proposal may then be submitted for review and modification to other faculty members who have knowledge and expertise in the area of the research proposal. After approval of the final proposal draft by the supervising professor, the proposal is submitted to the Committee on Graduate Studies for consideration of approval. Appointment of the Supervising Committee Once the student s thesis proposal is approved by COGS, the supervising professor and the candidate make recommendations to COGS regarding the composition of the Supervising Committee for the thesis research. The Supervising Committee must consist of four people (the supervising professor, two members from the Pharmacology Graduate Faculty, and one member from UTHSCSA who is not a member of the 26

27 Pharmacology Graduate Faculty). The supervising professor is designated as Supervising Professor and Chair of the Supervising Committee. The Supervising Professor will convene the Supervising Committee as necessary to discuss the progress of the thesis research and the projected future work with the candidate. The Supervising Committee must be fully informed of the research progress and be able to provide continued supervision throughout. COGS should receive reports of the research progress from the Supervising Committee after each of its meetings with the candidate. It will be the Supervising Committee s responsibility to guide the candidate through the thesis research and certify to COGS that the candidate has carried out a research investigation of the caliber appropriate for a M.S. thesis and has defended it satisfactorily. Upon selection of the Supervising Committee, the Chair of COGS will submit a completed Form 42 Composition of Supervising Committee The Master of Science Degree to the Graduate School Dean s Office. A copy of the proposed work must accompany the form. Each member of the Supervising Committee is required to sign the form to certify her/his approval to serve on the committee. Registration for Thesis Students on the M.S. degree track may register for the Thesis course (PHAR 6098) after the following actions have been taken: Approval of admission to candidacy for the M.S. degree by the Associate Dean Approval of the thesis research proposal by COGS Appointment of a Supervising Committee for the thesis research by COGS A candidate for the M.S. degree must register for one semester of thesis. Final Credit Hours A student must be registered for the semester or Summer session in which s/he graduates. If a student is registering only for final credit hours in preparation of a thesis and registers for no other courses, s/he is exempt from the minimum tuition requirement and pays tuition based upon the number of credit hours for which s/he is registered. The minimum number of final credit hours for the M.S. degree is one. Submission of the Thesis After members of the Supervising Committee agree that the research has progressed sufficiently for submission of the thesis, the draft of the thesis shall be submitted to the Supervising Professor and the other members of the Supervising Committee as well as the Graduate School Dean s office for review and recommendation for modification. The candidate should follow the guidelines for preparation of the thesis provided by the 27

28 Graduate School Dean s Office in Instructions for Preparation and Submission of Theses, Dissertations and Dissertation Abstracts. If an alternate format appears to be preferable, the candidate must obtain approval to use the alternate format from the Supervising Committee, COGS and the Dean. Final Oral Examination The Graduate School requires that the thesis be defended by the candidate in a Final Oral Examination conducted by the Supervising Committee. COGS may choose either of the options below as the format of the Final Oral Examination. Option 1: COGS may require that the thesis be defended in a formal Final Oral Examination scheduled through the Graduate School Dean s Office and open to all interested persons. The procedure for arranging this Final Oral Examination is the same as that for the Ph.D. Option 2: COGS may choose a less formal format that doesn t entail public notification from the Graduate School Dean s Office. In this case, the Supervising Committee submits a Request for Final Oral examination Form to the Chair of COGS. If approved, the request then goes to the Graduate School Dean s Office. Two copies of the abstract and the Vita should be submitted with the request for the candidate s files in the Registrar s Office and the Graduate School Dean s Office. The Supervising Committee members vote on the candidate s success or failure on the Examination; more than one vote for failure signifies failure on the Final Oral Examination. In the event of a failing performance, the Supervising Committee submits the Report on Final Oral Examination to COGS with recommendations regarding remedial action or further examinations. In this situation, COGS will decide what recommendation or other action to follow. If the student s performance in the Oral Examination is successful, the Supervising Committee submits the same report to the COGS, which then votes on whether to approve the recommendation of the Supervising Committee to grant the MS degree. Recommendation for Granting of the Degree Once COGS approves the favorable recommendation by the Supervising Committee, the Chairman of COGS submits the Report on Final Oral Examination to the GFC for consideration. The candidate then submits the final typed copy of the thesis (including the thesis Approval Page signed by the Supervising Committee members) to the Graduate School Dean s Office. The GFC will consider the recommendation for granting the degree when both the Report and the thesis copy have been received. If the recommendation for granting the degree is not approved, the Council will refer the matter to COGS with a recommendation for remedial action. If the recommendation is 28

29 approved, the Dean of the Graduate School of Biomedical Sciences will notify the President of the University of Texas Health Science at San Antonio that the candidate has fulfilled the requirements for the degree of Master of Science. Upon the candidate s certification by the President, the degree is conferred by The University of Texas System Board of Regents. 29

30 MISCELLANEOUS INFORMATION Graduate Teaching/Research Assistantship Stipends Graduate students who are enrolled full-time and who remain in good academic standing may receive a yearly stipend in the form of a graduate teaching/research assistantship as recommended by COGS to the department Chair. Currently, this stipend is $26,000 for all graduate students, and is guaranteed for five years, provided the student remains in good standing within the Department. The award of a graduate teaching/research assistantship stipend is reviewed annually by the COGS. Students who apply for and receive grant funding (e.g. a National Research Service Award {NRSA}) will be subsidized by the department if the grant funding doesn t match that of the stipend. Time to Degree A minimum of 72 semester credit hours is required for a Ph.D. degree. It is expected that full-time Ph.D. candidates will complete the requirements for the Ph.D. degree within a maximum of six years or within 130 credit hours. If a student is unable to complete the requirements for the degree within this time period, the student and the supervising professor may petition COGS for an extension. COGS will make a determination based upon evidence of adequate progress that would justify an extension. The Pharmacology Department has no obligation to financially support a graduate student for more than six years. In addition, students enrolled for more than 130 credit hours may be required to pay nonresident tuition for all subsequent semesters. Faculty Mentor A faculty mentor will be assigned to each first-year graduate student. In subsequent years, the dissertation supervisor serves as the student s academic advisor and dissertation supervisor. First year students also have a Peer Advisor chosen from the student body. Student Travel During their tenure in the graduate program, students will be eligible for a maximum of $750 in State funds to support travel to scientific meetings. This money is to be used within the first year before a student has selected a lab. At the time a lab is selected, any unused funds go back to the Department and the PI will be responsible for any needed travel funds. Prior to travel, students must petition COGS (in writing) for the use 30

31 of such travel funds. Students may use State funds to travel to meetings if they are in good academic standing and are presenting a paper/poster. Copying All students will be allowed a maximum of $80.00 (4 - $20.00 renewals) for copying from Departmental funds during each of the first two years in the program. Once the student has selected a Supervising Professor and entered a lab, copying costs become the responsibility of the Supervising Professor. Distribution of the COGS Meeting Minutes Distribution of the minutes of the meetings of the COGS is limited to the Graduate Faculty of the Pharmacology Graduate Program and the Graduate Student Representative. Payment for Tutorial Services A graduate student may not accept payment for tutorial services rendered to a student if the graduate tutor could potentially be involved in the student's evaluation through lecturing, grading of examinations, review of grades, etc. If no such potential conflict of interest exists, then the graduate student may tutor students for remuneration provided the graduate student first informs the tutee of the fee to be charged for the service. Proctoring of Examinations As part of their teaching assistantship responsibilities, graduate students may be asked to help the faculty proctor examinations in various Medical and Dental Pharmacology courses. Tuition All graduate students are classified as Teaching Assistants, and as such are eligible to be assessed the resident tuition rate throughout the academic program. However, in order to maintain resident status, out-of-state/country students must submit a Certificate of Employment prior to the census date of each term. This form can be obtained through the Graduate Academic Coordinator. 31

32 Health Insurance All UTHSCSA students are required to have major health insurance. A student health plan is available for purchase through United Health Care. Fees for this plan will be assessed on the student s tuition statement. If a student opts to subscribe to an alternative health insurance plan he/she must provide proof of the insurance coverage by submitting a UTHSCSA Health Insurance Coverage Information form and a copy of his/her insurance card prior to the tuition payment deadline each semester. Students with coverage through United Health Care are also required to submit this form each semester. The form can be obtained through the Graduate Academic Coordinator. 32

33 COURSE DESCRIPTIONS REQUIRED COURSES CSBL Experimental Design and Data Analysis (2 credits) Course Director: Dr. William Morgan Fall The purpose of the course is to provide an introduction to experimental design and statistical analysis. The emphasis of the course will be on the selection and application of proper tests of statistical significance. Practical experience will be provided in the use of both parametric and nonparametric methods of statistical evaluation. Among the topics to be covered are: data reduction, types of distributions, hypothesis testing, scales of measurement, chi square analysis, the special case of the comparison of two groups, analysis of variance, a posteriori multiple range tests, tests of the assumptions of parametric analyses, advanced forms of the analysis of variance, linear regression and correlation analysis. INTD 5000 Fundamentals of Biomedical Sciences (10 credits) Course Director: Dr. James Roberts Fall This is a core course covering the fundamentals of biochemistry, molecular biology, cell biology, microbiology, immunology, and organismal & systems biology. The course is designed for first year graduate students matriculating into the integrated, multidisciplinary graduate program. INTD Ethics in Research (0.5 credits) Course Director: Dr. Joel Baseman Spring All second-year graduate students are required by the Graduate School to take this course or its equivalent. This course will deal with topics relevant to ethics in scientific research. The course will be taught on a case study basis, dealing with real and hypothetical situations relevant to the conduct of scientific research. Topics discussed will include, but will not be limited to: data management, peer review, recognizing scientific misconduct, authorship and The University of Texas regulations relevant to human and animal research. 33

34 PHAR 5001 Pharmacology (4 credits) Course Director: Dr. Francis Lam Spring The course begins with basic pharmacologic principles applicable to all drugs. The remainder of the course addresses major drug classes that are discussed using prototype drugs. Drugs, which are exceptions to, or variations from, prototypes, are emphasized. The course emphasizes drug therapeutics, side effects, toxicity, precautions, contraindications and interactions that have particular relevance to dentistry. How knowledge of basic pharmacology can be used to assess drug manufacturers claims is illustrated by analyzing published drug advertisements. PHAR Principles of Pharmacology (3 Credits) Course Director: Dr. William Clarke Spring Principles of drug action; receptor classification and quantitation; dose-response relationships; cellular mechanisms of drug action; fundamental concepts of drugreceptor interactions; voltage-gated and ligand-gated ion channels; drug actions mediated by transduction and non-transduction enzymes; time course of drug action; absorption, distribution, biotransformation and elimination of drugs; pharmacokinetics; experimental approaches to drug action. PHAR Basics of Research Design (1.5 credits) Summer Course Director: Dr. Andrea Giuffrida The course aims at teaching first year graduate students fundamentals of research design and analysis of scientific literature to orient them with setting up scientific experiments and writing grant proposals. The course is divided in 3 sections: - Research Design: students are thought how to choose testable hypotheses, design an experiment and control variables. - Communicating scientific data: provides guidelines for communicating scientific data, writing a manuscript and reviewing scientific papers. - Getting scientific ideas funded: provides guidelines for the preparation of grant proposals. 34

35 PHAR Pharmacology Seminar (1 credit) Course Director: Dr. Tom Cunningham Fall/Spring Presentation and discussion of recent advances and research by staff, students, and outside scientists. Each graduate student is expected to register for Seminar each Fall or Spring semester the student is enrolled in graduate school. If a student is registered for nine (9) or more credit hours, the student need not register for Seminar hours. All students are required to attend each departmental Seminar and Journal Club each semester s/he is enrolled in graduate school regardless of whether or not s/he is registered for Seminar. Students may be required to sign in at each seminar in order to record her/his attendance. Receiving two or more unexcused absences at Seminar or Journal Club will result in the loss of travel funds and/or the student receiving a grade of Unsatisfactory for the course. Possible consequences of receiving a grade of Unsatisfactory for Seminar include, but are not limited to the following: 1) the Department could terminate the student s departmental funding; 2) student may be referred to the Chair of the Department for appropriate action; 3) student may be dismissed from the program. In addition, a student must petition COGS in writing if s/he would like for an absence to be excused. PHAR Special Problems in Pharmacology (1 credit) Course Director: Dr. Tom Cunningham Fall/Spring/Summer Students must complete two laboratory rotations in different laboratories by the end of the first year in the graduate program. Laboratory rotation mentors may be selected from the Graduate Faculty of the Pharmacology graduate program who have active research laboratories. Each rotation is a full-semester rotation. Students are expected to work at least 12 hours per week in their laboratory rotations during the Fall and Spring semesters and to work full-time in the laboratory in the Summer session. Students present a 15 minute post-laboratory rotation talk following completion of each laboratory rotation. Students are encouraged to contact their Special Problems supervisor who will assist them in the preparation and organization of the oral presentation. Students are expected to register for Pre-dissertation Research hours following completion of the second Special Problems Laboratory Rotation. A student may request permission to pursue a third Special Problems Laboratory Rotation, but may not register for more than 3 semesters of Special Problems. 35

36 PHAR Supervised Teaching (1 credit) Course Director: Dr. Tom Cunningham Fall/Spring/Summer The Graduate School requires that all graduate students register for supervised teaching. A student should register for this course upon registering for his/her first lab rotation. The requirement will be fulfilled through presentations of lab rotation data, Journal Club presentations, the oral Qualifying Exam, and the Dissertation proposal and defense. If a student wishes to have a more formal Supervised Teaching experience, opportunities might be available to lecture in the Dental Hygiene Pharmacology course under the supervision of the Course Director. PHAR 6097 Research (credit to be arranged) Course Director: Student s Faculty Advisor Fall/Spring/Summer Independent, original research under the direction of a faculty advisor. Following admission to candidacy, students register for research hours to maintain full-time student status. PHAR 6098 Thesis: MS Students (credit to be arranged) Course Director: Student s Faculty Advisor Fall/Spring/Summer Prerequisite: Admission to candidacy for the MS degree; approval of thesis research proposal by COGS; and appointment of a Supervising Committee for the thesis research by COGS Registration for at least one term is a Graduate School requirement for all MS candidates. PHAR 7099 Dissertation: PhD Students (credit to be arranged) Course Director: Student s Faculty Advisor Fall/Spring/Summer Prerequisite: Admission to candidacy for Doctor of Philosophy degree; approval of dissertation research proposal by COGS, GFC and the Dean; and approval by GFC and the Dean of the Supervising Committee for the dissertation research recommended by COGS. A student must register for at least two semesters of Dissertation prior to the anticipated graduation date, but there is no required number of credit hours for Dissertation. 36

37 ELECTIVE COURSES BIOC Cell Signaling Mechanisms (2 credits) Course Director: Dr. Jean Jiang Spring This course covers the molecular mechanisms of action of various extracellular mediators including hormones, neurotransmitters, growth factors, cytokines, etc. and cell signaling events. Several areas will be discussed including (1) mechanisms of mediator synthesis, (2) interaction of mediators with specific receptors, (3) modulation by mediators of various second messenger systems including cyclic nucleotides, inositol phospholipids, calcium, protein phosphorylation, ion flux, etc. and (4) intra- and intercellular mechanism for regulating mediator action. CSBL 6048 Molecular Biology of Aging (3 credits) Fall Course Director: Dr. Olivia Smith The purpose of this course is to provide students with the most up-to-date information on the current understanding of the aging process. This advanced interdisciplinary graduate course will be offered to students who wish to either specialize in or have a strong background in the interrelated areas of aging and age-related diseases. Faculty from the Departments of Cellular & Structural Biology, Physiology, Pharmacology and Medicine will be involved in teaching this course, which will cover the molecular and cell biology of aging, model systems used for aging studies, age related changes in organs and tissues and age related diseases. This course is an elective for all Departments. INTD 5040 Fundamentals of Neuroscience I: Molecular, Cellular, & Developmental Neuroscience (4 credits) Course Director: Dr. James Roberts Spring This course is intended to introduce students to a broad survey of the basics of molecular, cellular, and developmental neuroscience. The course is organized into a series of three modules: 1) Biochemical & Cellular Properties of Nervous System Cells; 2) Development of Neuronal Systems; and 3) Neurotransmission & Neuromodulation. Current topics and concepts are discussed in Discussion Sessions, which include student participation. 37

38 INTD 5043 Fundamentals of Neuroscience II: Systems Neuroscience (4 credits) Course Director: Dr. David Morilak Fall This course, the second component of our broad survey of the basics of neuroscience, begins at the level of the neural circuit, and guides the student through an understanding of increasingly complex levels of organization and function in the brain. Topics include neurotransmitter systems, sensory and motor function, motivated behavior, regulation and integration of autonomic, behavioral and emotional responses in the limbic system, higher order cognitive processes, and the neurobiological basis underlying some important psychiatric disorders and their treatment. INTD 5047 Neuroanatomy (1.5 credits) Course Director: Dr. William Morgan Fall The purpose of this course is to provide students with a practical working knowledge of the structure of both the peripheral and central nervous system. The emphasis will be on the organization of the human brain, although the brains of other species may also be included if appropriate for a specific brain region. The course will look at each of the individual components of the central nervous system in some depth but will also emphasize the complex integration of these various components into a functional brain. The topics covered in the course are specifically designed to mesh in time with those covered in Fundamentals of Neuroscience II describing the function of these areas. For this reason, it would be best if these two courses were taken concomitantly. The course will be didactic with digital images, models, and wet specimens included in the course. INTD 6041 Basic Science Resident Lecture Series in Neurology (1.5 credits) Course Director: Dr. Merrill Carolin Fall/Spring An interdisciplinary advanced elective in which students attend 20 lectures, selected from the full offering of daily one-hour lectures comprising the Neurology Residents Basic Sciences lecture series. These lectures cover a range of topics, such as Epilepsy, Movement Disorders, the Thalamus, Parkinson s Disease, Alzheimer s Disease, Stroke, Sleep, etc., all given from a clinical perspective. In addition, graduate students will have the opportunity to observe or participate in at least two enrichment activities related topically to the lectures they attend, which may include such settings as case presentations, diagnostic training sessions, or clinical observation sessions, again selected from the list of offerings in the Neurology Residents series. 38

39 PHAR Micro-electives (1 credit) Course Director: Dr. Tom Cunningham Fall/Spring/Summer Micro-electives are courses, which can be of any type ("tutorial" or original literature review, short (2 week) didactic, technique, etc). Complete course descriptions can be found on the Department of Pharmacology's web site. The terms in which the courses are offered may vary. Check the online list of courses each term to determine the offerings New Views on Monoaminergic Neurotransmission: Are Transporters Important? Course Director: Dr. Lynette Daws Ion Channelopathies in Neurological Disease Course Director: Dr. Russell Sanchez Historical Perspectives of Receptor Theory Course Director: Dr. William Clarke Cell Membrane Microdomains and Signaling Course Director: Dr. William Clarke Neuropeptide Metabolism Course Director: Dr. James Roberts Serotonin: From Soup (Transmission) to Nuts (Behavior) Course Directors: Drs. Alan Frazer & Julie Hensler Course no longer offered Neural Substrates of Regulatory Behaviors: Peptides and Monoamines Course Director: Dr. Tom Cunningham Current Issues in Basic Research on Mechanisms of Epilepsy Course Directors: Drs. José Cavazos, Robert Brenner, & Russell Sanchez Appetite Control: Adiposity Hormones and Neuropeptides Course Director: Dr. Xin-Yun Lu 39

40 PHAR 6020 Molecular & Pharmacological Basis of Therapeutics (2 credits) Fall Course Director: Dr. Francis Lam This course provides graduate students with current knowledge of how genetic variants can affect drug response and the potential to optimize drug therapy. Course format will include lectures, discussion of selected literature, individual student presentations, and development of a mini pharmacogenetic/genomic protocol and consent form to address a clinical/biomedical question mutually agree upon between course director and students. PHAR Molecular Pharmacology (2 Credits) Course Director: Dr. Feng Liu Spring This course is presented in a journal club/paper discussion format and will focus on the molecular aspects of pharmacology, with emphasis on molecular biology, biochemistry, and cell biology of a variety of physiological systems subjected to pharmacological manipulation. The topics to be discussed will include molecular mechanisms of drug action, signal transduction and regulation, molecular approaches and recent advances in various areas of molecular pharmacology. 40

41 THE FACULTY AND THEIR RESEARCH INTERESTS THE DEPARTMENT OF PHARMACOLOGY THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO Revised August

42 José E. Cavazos Assistant Professor of Medicine (Neurology) and Pharmacology M.D., Instituto Tecnologico y Estudios Superiores de Monterrey Ph.D., University of Wisconsin at Madison Office: (210) x4373 or (210) cavazosj@uthscsa.edu My laboratory studies activity-dependent plasticity in the hippocampal formation in the developing, adult, and aged brain using a variety of experimental models of epilepsy, seizures, and epileptogenesis. Previous studies from my laboratory have shown that repeated seizures induce progressive neuronal death and axon sprouting that permanently alter the hippocampal circuitry lending it more susceptible to additional seizures and memory dysfunction. We currently are investigating the molecular mechanisms that link the synchronous neuronal hyperexcitability with these morphological events including the role of caspases using in-vivo models and in-vitro organotypic hippocampal slice cultures. We investigate the features of seizure-induced axon sprouting in other limbic circuitries using anatomical tracing techniques, and their electrophysiological consequences in the neuronal excitability of the abnormally connected circuitry using brain slices. Lastly, we are evaluating several antagonists at the various steps in this cascade that leads to circuit plasticity with the aim of identifying the crucial steps in the epileptogenic process amenable to novel pharmacological targets for a better treatment of seizures and epilepsy. Selected Publications Cavazos, J.E., S.M. Jones., D.J. Cross. Sprouting and Synaptic Reorganization in the Subiculum and CA1 Region of the Hippocampus in Acute and Chronic Models of Partial-Onset Epilepsy Neuroscience 126: , Cavazos, J.E., Sanchez R. Mechanisms of Seizures and Epilepsy. Chapter 2 of the Epilepsy: Scientific Foundations of Clinical Practice, edited by Rho JM, Sankar R, Cavazos JE (Eds.) Marcel, Dekker Inc. pp. 4-20, ISBN Cavazos, J.E., P. Zhang, R. Qazi, T.P. Sutula. (2003) Ultrastructural Features of Sprouted Mossy Fiber Synapses in Kindled and Kainic Acid-Treated Rats. Journal of Comparative Neurology 458: , Cross, D, Diep, Y., Zhang, K., Cavazos, J. Neonatal Status Epilepticus induces Sprouting and Synaptic Reorganization of the CA1 to Subiculum pathway in the Hippocampus. Soc. Neurosci. Abstr. 29: 211.2, Cavazos JE, Kanske J, Perez J, Garcia M. Neuroprotective effects of topiramate in the kainic acid model of status epilepticus. Epilepsia 43 (Suppl. 7):15 (Abst ),

43 William P. Clarke Associate Professor of Pharmacology Ph.D., Wayne State University School of Medicine Office: (210) Work in my lab centers on questions concerning the molecular nature of drug efficacy and the cellular mechanisms by which efficacy can be regulated. An understanding of the nature of drug efficacy and the factors by which it is regulated is essential for the design of rational treatment regimens in clinical situations. Drug efficacy is defined as the ability of a drug to produce a response. According to traditional receptor theory (see equation #1), the magnitude of an effect (E) produced when an agonist at a specified concentration ([A]) interacts with a receptor is a function (ƒ) of the stimulus (S) produced by the agonist and depends upon 4 factors. Two of these are chemical properties of the agonist itself unique for each ligand-receptor pair; the affinity related parameter, K A, and "intrinsic efficacy" ε (ε describes the capacity of a drug to produce a receptor "stimulus" {which can be thought of as a conformational change in the receptor} which is transmitted to the signal transduction components of the cell). The remaining two parameters are cell or tissue dependent properties; receptor density, R T and a function, ƒ, that describes the efficiency of signal transduction. Thus, cellular mechanisms that influence drug efficacy are those that regulate any or all of these four parameters. E = f( S)= f ε A R T 1 + K A A [ ] Equation #1 The drug property, intrinsic efficacy, according to traditional receptor theory, is a unique for each drug-receptor pair and is independent of the response measured. Thus, if a drug produced a 50% response (relative to that of a reference drug) for one measure, it must also produce a 50% response for all measures coupled to a receptor. Recent evidence from our, laboratory, and others, challenges that assertion. Work in our lab has centered upon understanding the mechanisms by which drug intrinsic efficacy is response-dependent. Our working hypothesis is that drugs can elicit unique spectra of receptor conformations that have differential capacities to activate signaling mechanisms in cells. Current models of receptor function are based on the existence of receptors in equilibrium between multiple conformations or states that display differential degrees of activity toward cellular signaling mechanisms in the absence of a ligand. One consequence of which is that receptors can activate signaling mechanisms in cells in the absence of a ligand (constitutive receptor activity) and some drugs have the capacity to turn off, as well as turn on, receptors. Drugs that reduce constitutive receptor activity are called inverse agonists and are said to have negative intrinsic efficacy. Work 43

44 in our lab has been devoted to understanding the physiological and pharmacological consequences of inverse agonism and how it can be regulated. Cellular factors involved in the regulation of drug efficacy that are under investigation include the consequences of activation of other receptor systems on cells (so-called "cross-talk" between receptor systems) and mechanisms of desensitization (homologous and heterologous). Furthermore, the impact of subcellular localization of receptors and signaling molecules with respect to membrane microdomains on drug efficacy is also under study. Selected Publications Berg, K.A., Evans, K.L.J., Cropper, J.D. and Clarke, W.P. Temporal regulation of agonist efficacy at 5-HT 1A and 5-HT 1B receptors. J. Pharmacol Exp Ther 302: , Berg KA, Clarke WP. Regulation of 5-HT(1A) and 5-HT(1B) receptor systems by phospholipid signaling cascades. Brain Res Bull Nov 15;56(5): Review. Berg KA, Stout BD, Maayani S, Clarke WP. Differences in rapid desensitization of 5- hydroxytryptamine2a and 5-hydroxytryptamine2C receptor-mediated phospholipase C activation. J Pharmacol Exp Ther Nov;299(2): Berg KA, Cropper JD, Niswender CM, Sanders-Bush E, Emeson RB, Clarke WP. RNAediting of the 5-HT(2C) receptor alters agonist-receptor-effector coupling specificity. Br J Pharmacol Sep;134(2): Evans KL, Cropper JD, Berg KA, Clarke WP. Mechanisms of regulation of agonist efficacy at the 5-HT(1A) receptor by phospholipid-derived signaling components. J Pharmacol Exp Ther Jun;297(3): Clarke, W.P. and R.A. Bond. The elusive nature of intrinsic efficacy. Trends Pharmacol. Sci. 19: , Tom Cunningham Associate Professor of Pharmacology Ph.D., University of Iowa Office: (210) cunninghamt@uthscsa.edu We study the role of the central nervous system in body fluid homeostasis and blood pressure regulation and how neuroplasticity in these systems contributes to chronic disease states such as hypertension, congestive heart failure, and the syndrome of inappropriate antidiuretic hormone release. Specifically we are interested in the integration of hormonal factors such as circulating angiotensin and neural input from baroreceptors and volume receptors and how this interaction might influence 44

45 vasopressin release, sympathetic outflow, and the ingestion of fluid and salt. To pursue this type of research we employ an integrative approach that includes in vivo electrophysiology, immunohistochemistry, neuroanatomical tract tracing, molecular biology, and measuring salt and water metabolism. Selected Publications Gottlieb HB, Fleming T, JI LL, and Cunningham JT. (2007) Identification of CNS sites involved in the water diuresis response elicited by central microinjection of nociceptin/orphanin FQ in conscious rats via c-fos and ICER immunocytochemistry. J Neuroendocrinol (in press). Ji LL, Gottlieb HB, Penny ML, Fleming T, Toney GM, and Cunningham JT. (2007) Differential effects of water deprivation and rehydration on Fos and FosB/DeltaFosB staining in the rat brainstem. Exp. Neurol., 203: Cunningham JT, Herrera-Rosales M, Martinez MA, and Mifflin S. (2007) Identification of active central nervous system sites in renal wrap hypertensive rats. Hypertension, 49: Mueller PJ, Sullivan MJ, Grindstaff RR, Cunningham JT, and Hasser EM. (2006) Regulation of plasma vasopressin and renin activity in conscious hindlimb-unloaded rats. Am J Physiol Regul Integr Comp Physiol, 291:R Mueller PJ, Foley CM, Heesch CM, Cunningham JT, Zheng H, Patel KP, and Hasser EM. (2006) Increased nitric oxide synthase activity and expression in the hypothalamus of hindlimb unloaded rats. Brain Res. 1115(1): Gottlieb HB, Ji LL, Jones H, Penny ML, Fleming T, and Cunningham JT. (2006) Differential effects of water and saline intake on water deprivation-induced c-fos staining in the rat. Am J Physiol Regul Integr Comp Physiol, 290:R Lohmeier TE, Hildebrandt DA, Warren S, May PJ, and Cunningham, JT. (2005) Recent insights into the interactions between the baroreflex and the kidneys in hypertension. Am J Physiol Regul Integr Comp Physiol, 288:R Ji LL, Fleming T, Penny ML, Toney GM, and Cunningham JT (2005). Effects of water deprivation and rehydration on c-fos and FosB staining in the rat supraoptic nucleus and the lamina terminalis region. Am J Physiol Regul Integr Comp Physiol, 288:R Lynette C. Daws Associate Professor of Physiology and Pharmacology Ph.D., Flinders University of South Australia, Australia Office: (210) daws@uthscsa.edu 45

46 The broad area of my research is studying the function and regulation of biogenic amine transporters (the serotonin, dopamine and norepinephrine transporters). Understanding how these transporters function is important in that they are pivotal in controlling the extracellular concentration of biogenic amines and hence, neurotransmission. Moreover, they are the primary site of action for numerous psychotherapeutic and addictive drugs. One of my primary research interests relates to the serotonin transporter. In humans, a polymorphism of the gene encoding the serotonin transporter leads to its reduced expression. This polymorphism has been linked to a number of disorders including alcoholism and depression. Moreover, individuals with this polymorphism appear to respond differently to drug treatment. We are using mice with a genetically induced reduction in the density of the serotonin transporter (heterozygote serotonin transporter knockout mice, which express 50% fewer serotonin transporters than the "normal", wildtype mouse) to investigate neuroadaptive changes associated with reduced expression of the transporter. We are further investigating the interaction that occurs between stress, serotonin transporter genotype and predisposition to alcoholism. Another major focus of our studies is the mechanism of MDMA ("Ecstasy"), paramethoxyamphetamine, amphetamine and cocaine at the dopamine and serotonin transporters. The acute and long term effects of these drugs on transporter function in vivo are being studied. In addition, we have more recently demonstrated that hormones, such as insulin, can influence the activity of the dopamine transporter. Importantly, we have found that insulin status dictates responsiveness to certain drugs of abuse. Thus, it appears that insulin can profoundly affect dopamine reward circuitry in brain. We are currently investigating the mechanism through which this occurs. These data have important implications for understanding the high-comorbidity of eating disorders and drug abuse as well as food "addictions," which may lead to obesity. On a more fundamental level, we are interested in studying how biogenic amine transporters are regulated by receptors. We are currently investigating the role of the 5- HT 1B autoreceptor, alpha-adrenoceptors and adenosine receptors in regulating activity of the serotonin transporter and of the D2 autoreceptor in regulating activity of the dopamine transporter. We implement several state-of-the-art techniques including in vivo high-speed chronoamperometry as well as a variety of molecular and behavioral approaches. Selected Publications Wiedholz, L., Owens, W.A., Horton, R.E., Feyder, M., Hefner, K.M., Sprengel, R., Daws, L.C. # and Holmes, A. # (in press) Mice lacking the AMPA GluR1 receptor exhibit hyperdopaminergia and "schizophrenia-related" behaviors. Molecular Psychiatry. # contributed equally Zhu, C-B., Steiner, J.A., Munn, J.L., Daws, L.C., Hewlett, W.A., and Blakely, R.D. (2007) Rapid stimulation of presynaptic serotonin transport by A3 adenosine receptors. Journal of Pharmacology and Experimental Therapeutics. E-Pub ahead of print, April

47 Daws, L.C., Munn, J.L., Valdez, M.F., Frosto-Burke, T., and Hensler, J.G. (2007) Serotonin transporter function, but not expression, is dependent on brain derived neurotropic growth factor (BDNF): In vivo studies in BDNF-deficient mice. Journal of Neurochemistry 101: Price, D., Owens, W.A., Gould, G.G., Frazer, A., Roberts, J.L., Daws, L.C., and Giuffrida, A. (2007) Cannabinoids affect dopamine transporter activity in mouse dorsal striatum. Journal of Neurochemistry 101: Sevak, R., Owens, W.A., Koek, W., Galli, A., Daws, L.C. # and France, C.P. # (2007) Raclopride prevents normalization of amphetamine stimulated locomotor activity and dopamine clearance in STZ-treated rats. Journal of Neurochemistry 101: # contributed equally Callaghan, P.D., Owens, W.A., Javors, M.A., Sanchez, T.A., Jones, D., Irvine, R.J., and Daws, L.C. (2007) In vivo analysis of serotonin clearance in rat hippocampus reveals that repeated administration of p-methoxyamphetamine (PMA), but not 3,4- methylenedioxymethamphetamine (MDMA), leads to long-lasting deficits in serotonin transporter function. Journal of Neurochemistry 100: Boyce-Rustay, J.M., Wiedholz, L.M., Millstein, R., Carroll, J., Murphy, D.L., Daws, L.C. and Holmes, A. (2006) Ethanol-related behaviors in serotonin transporter knockout mice. Alcoholism: Clinical and Experimental Research 30:1-9. Callaghan, P.D., Farrand, K., Salem, A., Hughes, P., Daws, L.C., and Irvine, R.J. (2006) Repeated administration of the substituted amphetamine p- methoxyamphetamine (PMA) produces reductions in cortical 5-HT transporter binding but not 5-HT content, unlike 3,4-methylenedioxymethamphetamine. European Journal of Pharmacology 546: Fog, J.U., Khoshbouet, H., Holy, M., Owens, W.A., Vaegter, C.B., Sen, N., Nikandrova, Y., McMahon, D.G., Colbran, R.J., Daws, L.C., Sitte, H.H., Javich, J.A., Galli, A. and Gether, U. (2006) Calmodulin kinase II interacts with the dopamine transporter C- terminus to regulate amphetamine-induced reverse transport. Neuron 51(4): Daws, L.C., Montañez, S., Munn, J.L., Owens, W.A., Baganz, N.L., Boyce-Rustay J.M., Millstein, R., Wiedholz, L.M., Murphy, D.L. and Holmes, A. (2006) Ethanol inhibits clearance of brain serotonin by a serotonin transporter independent mechanism. Journal of Neuroscience 26: **Research Highlight featured in August 2006 edition of Nature Reviews Neuroscience Vol 7:593, "Under the Influence" by Daniel McGowen, Ph.D. Owens, W.A., Sevak, R., Galici, R., Chang, X., Javors, M.A., Galli, A., France, C.P., and Daws, L.C. (2005). Deficits in dopamine clearance and locomotion in hypoinsulinemic rats unmask novel modulation of dopamine transporters by amphetamine. Journal of Neurochemistry 94: Callaghan, P.D., Irvine, R.J., and Daws, L.C. (2005). Differences in the in vivo dynamics of neurotransmitter release and uptake after acute para- 47

48 methoxyamphetamine and 3,4 methylenedioxymethamphetamine revealed by chronoamperometry. Neurochemistry International 47: Daws, L.C., Moñtanez, S., Owens, W.A., Gould, G.G., Frazer, A., Toney, G.M., and Gerhardt, G.A. (2005) Transport mechanisms governing serotonin clearance in vivo revealed by high speed chronoamperometry. Journal of Neuroscience Methods - Special Issue, Studying monoamine transporters: Beyond hypermonoamineaemia. 143: Montañez, S., Owens, W.A., Gould, G.G., Murphy, D.L. and Daws, L.C. (2003) Exaggerated effects of fluvoxamine in heterozygote serotonin transporter knockout mice. Journal of Neurochemistry 86: Ansah, T.A., Ramamoorthy, S., Montañez, S., Daws, L.C. and Blakely, R.D. (2003) Calcium-dependent inhibition of synaptosomal serotonin transport by the alpha 2- adrenergic receptor agonist UK Journal of Pharmacology and Experimental Therapeutics 305: Daws, L.C., Callaghan, P.D., Morón, J., Kahlig, M.K., Shippenberg, T.S., Javitch, J.A. and Galli, A. (2002) Cocaine increases dopamine uptake and cell surface expression of dopamine transporters. Biochemical and Biophysical Research Communications 290(5): Lily Q. Dong Assistant Professor of Cellular & Structural Biology and Pharmacology Ph.D., Iowa State University Office: (210) dongq@uthscsa.edu Insulin resistance is a primary contributing factor in the pathogenesis of type 2 diabetes. This condition is characterized by the loss of insulin sensitivity in tissue, resulting in an impairment of glucose breakdown in cells, an unregulated production of glucose in hepatic cells, and a reduction of glucose uptake in skeletal muscle, resulting in a greatly increased glucose level in the bloodstream. Recently a new hormone has been identified in the human body known as adiponectin. This hormone is secreted by adipose tissue and is released into the bloodstream. The serum concentration of adiponectin is significantly reduced in type 2 diabetic and obese patients. A number of studies have shown that adiponectin is an insulin sensitizer by enhancing insulin sensitivity, which has the potential to be used therapeutically in the treatment of type 2 diabetes and obesity. However, the molecular mechanism governing adiponectin action is largely unknown. Our research interest is focused on 1) the elucidation of the molecular pathway(s) mediating adiponectin signaling in cells, 2) the investigation of the molecular mechanism regulating adiponectin levels in the human body, and 3) the molecular mechanism of the cross-talk between Insulin signaling pathway and Adiponectin signaling pathway. We have found that APPL1, an adaptor protein with multiple 48

49 function domains, is a signaling molecule immediate binding to adiponectin receptors, and positively mediate adiponectin signaling in muscle cells (Mao et al., 2006, Nat. Cell Biol., 8: ). The findings from our studies will provide potential mechanisms behind insulin resistance and the development of type 2 diabetes. Selected Publications: (Publications before 1997 were under the name of Dong, Q.) Li, J., Mao, X., Dong, L.Q., Liu, F., and Tong, L. (2007) Crystal structure of the BAR- PH and PTB domain of human APPL1. Structure, 15, Wang, C., Mao, X., Wang, L., Liu, M., Wetzel, M., Guan, K-L, Dong, L. Q., and Liu, F. (2007). Crosstalk between adiponectin and insulin signaling pathways: a molecular mechanism for adiponectin as an insulin sensitizer. J. Biol. Chem. 282, Riojas, R. A., Kikani, C. K., Wang, C., Mao, X., Zhou, L., Langlais, P. R., Hu, D., Roberts, JL, Dong, L. Q., and Liu, F. (2006). Fine-tuning PDK1 activity by phosphorylation at Ser163. J. Biol. Chem. 281, Mao, X., Kikani, C. K., Riojas, R. A., Langlais, P., Wang, L., Ramos, F. J., Fang, Q., Christ-Roberts, C.Y., Hong, J.Y., Kim, R. Y., Liu, F., and Dong, L. Q. (2006). APPL1 bonds to adiponectin receptors and mediates adiponectin signaling and function. Nature Cell Biology. 8, (High lighted article on cover page) (Research Highlight Commentary in Cell Metabolism (2006), 4, 5-6) Ramos, F. J., Langlais, P. R., Hu, D., Dong, L. Q., and Liu, F. (2006) Grb10 meiates insulin-stimulated degradation of the insulin receptor: a mechanism of negative regulation. Am J Physiol Endocrinol Metab. 290, E1262-E1266. Luo, M., Reyna, S.M., Wang, L., Yi, Z.P., Carroll, C.A., Dong, L.Q., Langlais, P., Weintraub, S.T., and Mandarino, L.J. (2005) Identification of IRS-1 Serine/Threonine Phosphorylation Sites Using Mass Spectrometry Analysis: Regulatory Role of Serine Endocriology, 146, Langlais, P., Wang, C., Dong, L. Q., Carroll, C. A., Weintraub, S. T., and Liu, F. (2005) Phosphorylation of Grb10 by Mitogen-Activated Protein Kinase: Identification of Ser150 and Ser476 of human Grb10zeta as Major Phosphorylation Sites. Biochemistry, 44, Lim, M. A., Moon, S.Y., Zheng, Y., Wu, H., Dong, L.Q., and Liu, F. (2004) Roles of PDK-1 and PKN in regulating cell migration and cortical actin formation of PTENdeficient cells. Oncogene, 23, Langlais, P., Dong, L. Q., Ramos, F. J., Hu, D., Li, Y., Quon, M. J., and Liu, F. (2004). Negative regulation of insulin-stimulated MAP kinase signaling by Grb10. Mol. Endo. 49

50 18, Lim, M. A., Kikani, C. K., Wick, M. J., and Dong, L. Q. (2003). Nuclear translocation of 3 -phosphoinositide-dependent kinase-1: a potential regulatory mechanism for PDK-1 function. Proc. Natl. Acad. Sci. USA. 100, Charles France Professor of Pharmacology and Psychiatry Ph.D., University of Michigan Office: (210) france@uthscsa.edu Research in my laboratory focuses on interactions between behavior and pharmacology as those interactions influence the abuse liability of drugs. One major goal of the laboratory has been to understand how the subjective effects of drugs change as a consequence of certain behavioral and pharmacologic histories. This laboratory has developed behavioral procedures (drug discrimination) that are sensitive to the withdrawal-precipitating effects of antagonists and we use these procedures to study the development of dependence and the expression of withdrawal as well as how these phenomena can be modified by various pharmacologic and behavioral manipulations. One unifying theme of research in this laboratory is the use of receptor theory, which provides a framework for the planning, execution and interpretation of behavioral studies with drugs. Thus, many of our studies attempt to differentiate among drugs on the basis of their efficacy and selectivity, thereby identifying the pharmacologic characteristics of drugs that are most important for particular behavioral effects (e.g., reinforcing effects). Current areas of research include the following: studies on the mechanism of action, abuse and dependence liability of GHB and related "club drugs"; the role of insulin receptor pathways in regulating dopamine transporter activity and sensitivity to stimulants; GABA receptor heterogeneity and the dependence liability of sedative/hypnotics; and the influence of physical dependence on the reinforcing effects of opioids. Selected Recent Publications Ercil, N.E., & France, C.P. (2003) Amphetamine-like discriminative stimulus effects of ephedrine and its stereoisomers in pigeons. Experimental and Clinical Psychopharmacology, 11, 3-8. Galici, R., Galli, A., Jones, D.J., Sanchez, T.A., Saunders, C., Frazer, A., Gould, G.G., Lin, R.Z., & France, C.P. (2003) Selective decreases in amphetamine selfadministration and regulation of dopamine transporter function in diabetic rats. Neuroendocrinology, 77,

51 McMahon, L.R., & France, C.P. (2003) Discriminative stimulus effects of positive GABA A modulators and other anxiolytics, sedatives, and anticonvulsants in untreated and diazepam-treated monkeys. Journal of Pharmacology and Experimental Therapeutics, 304, Carter, L.P., Flores, L.R., Wu, H., Chen, W., Unzeitig, A.W., Coop, A., & France, C.P. (2003) The role of GABA B receptors in the discriminative stimulus effects of γ- hydroxybutyrate in rats: time course and antagonism studies. Journal of Pharmacology and Experimental Therapeutics, 305, Wu, H., Zink, N., Carter, L.P., Mehta, A.K., Hernandez, R.J., Ticku, M.K., Lamb, R., France, C.P., & Coop, A. (2003) A tertiary alcohol analog of γ-hydroxybutyric acid as a specific γ-hydroxybutyric acid receptor ligand. Journal of Pharmacology and Experimental Therapeutics, 305, Sell, S.L., & France, C.P. (2002) Cocaine and amphetamine attenuate the discriminative stimulus effects of naltrexone in opioid-dependent rhesus monkeys. Journal of Pharmacology and Experimental Therapeutics, 301, Alan Frazer Chair of Pharmacology Professor of Pharmacology and Psychiatry Ph.D., University of Pennsylvania Office: (210) frazer@uthscsa.edu My primary research interest is the mechanisms of action of antidepressants. Most often, an in vivo approach is taken whereby measurements are made of effects produced by various types of antidepressants on noradrenergic or serotonergic neurons, on neurochemical or behavioral responses elicited by these neurotransmitters, or on their receptors. Neuroanatomical localization of drug-induced effects is emphasized by employing techniques such as quantitative autoradiography, immunohistochemistry, and in vivo voltammetry. Most of our recent work has used the latter technique to measure the rate of clearance of serotonin from extracellular fluid (ECF) in discrete regions of rat brain. Our lab is one of the few in this country that uses this technique to do this. The clearance of serotonin is primarily a reflection of the functioning of the serotonin transporter (SERT), a membrane protein that is a key target for drugs such as fluoxetine (Prozac). Our results demonstrate differences in the biogenic amine transporters responsible for the clearance of serotonin in different regions of brain. We also found that SERT function is desensitized upon chronic treatment of rats with selective serotonin reuptake inhibitors (SSRIs) such as sertraline (Zoloft) or paroxetine (Paxil). This downregulation had a significantly greater inhibitory effect on the clearance of serotonin from extracellular fluid than acute blockade of the SERT with SSRIs. 51

52 Importantly, it took about days for such downregulation to occur, a time when behavioral improvement that these drugs cause in depressed patients becomes recognizable. Selective norepinephrine reuptake inhibitors, such as the antidepressant desipramine, produce a downregulation of the norepinephrine transporter (NET), but do not cause this effect on the SERT. We have begun recently to study cognitive and emotional behaviors in animal "models" of depression to begin to integrate psychological theories of depression with biological processes in brain affecting relevant behaviors and antidepressant effects. Research Associates The research in my laboratory is currently being carried out by Dr. Saloua Benmansour (Research Instructor) and Dr. Georgianna Gould (Postdoctoral Fellow). Societal Affiliations Dr. Frazer is a member of numerous societies including the American Society of Pharmacology and Experimental Therapeutics, the American College of Neuropsychopharmacology, the Collegium Internationale Neuro- Psychopharmacologicum, and the Society of Neuroscience. He has been awarded a Merit Award from NIH and has been a Career Scientist of the Department of Veterans Affairs. In addition to serving on the editorial boards of several journals, he is currently the field editor for preclinical neuropsychopharmacology of the International Journal of Neuropsychopharmacology. Selected Publications Gould, G.G., Javors, M.A., Frazer, A.: Effect of chronic administration of duloxetine on serotonin and norepinephrine transporter binding sites in rat brain. Biological Psychiatry, 61(2): , Gould, G.G., Altamirano, A.V., Javors, M.A., Frazer, A.: A comparison of the chronic treatment effects of venlafaxine and other antidepressants on serotonin and norepinephrine transporters. Biological Psychiatry. 59: , Lu, X-Y., Kim, C.S., Frazer, A., Zhang, W.: Leptin: A potential novel antidepressant. Proc. Natl. Acad. Sci. (USA). 103: , Frazer, A., Morilak, D.A.: What should animal models of depression model? Neuroscience and Biobehavioral Reviews, 29: , Daws, L.C., Montanex, S., Owens, W. Anthony, Gould, G., Frazer, A., Toney, G., Gerhardt, G.: Transport mechanisms governing serotonin clearance in vivo revealed by high speed chronoamperometry. Journal Neurosci. Methods. 143: 49-62, Benmansour, S., Altamirano, A., Jones, D.J., Sanchez, T.A., Gould, G.C., Pardon, M.- C., Morilak, D.A., Frazer, A.: Regulation of the norepinephrine transporter by chronic administration of antidepressants. Biol. Psychiat., 55: , Morilak, D.A., & Frazer, A.: Antidepressants and brain monoaminergic systems. A 52

53 dimensional approach to understanding their behavioral effects in depression and anxiety disorders. Int. J. Neuropsychopharmacology. 7: , Lisa Gerak Assistant Professor of Pharmacology Ph.D., Louisiana State University Office: (210) Current research projects include studies on the behavioral pharmacology of compounds that modulate the γ-aminobutyric acid A (GABA A ) receptor complex with an emphasis on the effects of ethanol and neuroactive steroids. GABA A modulators can vary in efficacy and selectivity for the various modulatory sites on the GABA A receptor complex as well as for different subtypes of GABA A receptors. Differences in the behavioral effects of GABA A modulators are assessed using procedures that examine acute (discriminative stimulus effects) and chronic (tolerance, dependence, withdrawal) effects of drugs. The general goals of this research program are: to develop quantitative methods for assessing the effects of chronic treatment with GABA A modulators; to evaluate fundamental differences in the behavioral effects of drugs that act at different modulatory sites on GABA A receptors; to understand dependenceinduced changes in GABA A receptor function; to determine whether novel GABA A modulators might be useful pharmacotherapies for ethanol abuse; and to assess the applicability of receptor theory for interpreting behavioral effects of GABA A modulators. Selected publications Gerak, L.R. and France, C.P. (2007) Time-dependent decreases in apparent pa 2 values for naltrexone studied in combination with morphine in rhesus monkeys. Psychopharmacology, epub ahead of print. Leonard, S.T., Gerak, L.R., Gurkovskaya, O., Moerschbaecher, J.M. and Winsauer, P.J. (2006) Effects of gamma-hydroxybutyric acid and flunitrazepam on ethanol intake in male rats. Pharmacology, Biochemistry and Behavior, 85: Quinton, M.S., Gerak, L.R., Moerschbaecher, J.M. and Winsauer, P.J. (2006) Effects of pregnanolone in rats discriminating cocaine. Pharmacology, Biochemistry and Behavior, 85: McMahon, L.R., Gerak, L.R. and France, C.P. (2006) Efficacy and the discriminative stimulus effects of negative GABA A modulators, or inverse agonists, in diazepamtreated rhesus monkeys. Journal of Pharmacology and Experimental Therapeutics, 318:

54 Quinton, M.S., Gerak, L.R., Moerschbaecher, J.M. and Winsauer, P.J. (2005) Interaction of cocaine with positive GABA(A) modulators on the repeated acquisition and performance of response chains in rats. Psychopharmacology, 181: Gerak, L.R., Hicks, A.R., Winsauer, P.J., and Varner, K.J. (2004) Interaction between 1,4-butanediol and ethanol on operant responding and the cardiovascular system. European Journal of Pharmacology, 506: Gerak, L.R., Stevenson, M.W., Winsauer, P.J., and Moerschbaecher, J.M. (2004) Effects of pregnanolone alone and in combination with other positive GABA A modulators on complex behavior in rats. Psychopharmacology, 173: Gerak, L.R., Gauthier, C.A., and France, C.P. (2003) Discriminative stimulus and antinociceptive effects of dihydroetorphine in rhesus monkeys. Psychopharmacology, 166: McMahon, L.R., Gerak, L.R., Carter, L., Ma, C., Cook, J.M., and France, C.P. (2002) Discriminative stimulus effects of benzodiazepine (BZ) 1 receptor-selective ligands in rhesus monkeys. Journal of Pharmacology and Experimental Therapeutics, 300: McMahon, L.R., Gerak, L.R., and France, C.P. (2001) Potency of positive γ- aminobutyric acida modulators to substitute for a midazolam discriminative stimulus in untreated monkeys does not predict potency to attenuate a flumazenil discriminative stimulus in diazepam-treated monkeys. Journal of Pharmacology and Experimental Therapeutics, 298: Gerak, L.R., France, C.P., Woolverton, W.L., Nader, M.A., Patrick, G.A., Harris, L.S., Winger, G. and Woods, J.H. (2001) Behavioral effects of flunitrazepam: reinforcing and discriminative stimulus effects in rhesus monkeys and prevention of withdrawal signs in pentobarbital-dependent rats. Drug and Alcohol Dependence, 63: Lelas, S., Gerak, L.R. and France, C.P. (2000) Antagonism of the discriminative stimulus effects of positive γ-aminobutyric acid A modulators in rhesus monkeys discriminating midazolam. Journal of Pharmacology and Experimental Therapeutics, 294: Gerak, L.R. and France, C.P. (1999) Discriminative stimulus effects of flumazenil in untreated and diazepam-treated rhesus monkeys. Psychopharmacology, 146: Gerak, L.R., Moerschbaecher, J.M., Bagley, J.R., Brockunier, L.L., and France, C.P. (1999) Effects of a novel fentanyl derivative on drug discrimination and learning in rhesus monkeys. Pharmacology, Biochemistry and Behavior, 64:

55 Woolverton, W.L., Rowlett, J.K., Winger, G., Woods, J.H., Gerak, L.R., and France, C.P. (1999) Evaluation of the reinforcing and discriminative stimulus effects of γ- hydroxybutyrate in rhesus monkeys. Drug and Alcohol Dependence, 54: Lelas, S., Gerak, L.R., and France, C.P. (1999) Discriminative-stimulus effects of triazolam and midazolam in rhesus monkeys. Behavioural Pharmacology, 10: Andrea Giuffrida Assistant Professor of Pharmacology Ph.D., University of Catania (Italy) Office: (210) My laboratory is interested in the role played by the endogenous cannabinoid system in regulating psychomotor functions. The endocannabinoids are a family of naturally occurring lipids that mimic the effects of marijuana by stimulating specific receptors expressed in the brain (cannabinoid receptors). CB 1 cannabinoid receptors are particularly abundant in areas of the central nervous system that are critical for the regulation of motor behaviors, such as the basal ganglia In addition, the endocannabinoids may serve as an inhibitory feedback signal to counteract dopamineinduced motor activation. Our recent reports indicate that the endocannabinoid system represents a new pharmacological target for the treatment of diseases characterized by dysregulation of dopamine transmission, such as Parkinson s disease and schizophrenia. We integrate neurochemistry and behavioral pharmacology to study endocannabinoid transmission and disturbances in animal models of neurological and psychiatric disorders including Parkinson s disease, essential tremor, schizophrenia and druginduced dyskinesias. Our laboratory is also interested in the implantation of tissueengineered constructs to repair the nigro-striatal pathway in Parkinson s disease. Selected Publications Price D.A., Owens W.A., Gould G.G., Frazer A., Roberts J.L., Daws L.C., Giuffrida A. Cannabinoids inhibit dopamine transporter activity in mouse dorsal striatum. J. Neurochem 101: (2007). Schreiber D., Barlfinger S., Nolden B.M., Gerth C.W., Jaehde U., Schoemig E., Klosterkoetter J., Giuffrida A., Astarita G., Piomelli D., Leweke F.M. Determination of anandamide and other fatty acid ethanolamides in human serum buy electrospray tandem mass spectrometry. Anal Biochem. 361: (2007). Leweke F.M., Giuffrida A., Koethe D., Schreiber D., Nolden B.M., Neatby N.A., Schneider M., Gerth C., Klosterkoetter J., Piomelli D. Anandamide levels in CSF of 55

56 patients with first-episode schizophrenia or schizophreniform psychosis: relation to cannabis use. Schizophrenia Res. (2007, in press). Ferrer B, Bermudez-Silva FJ, Bilbao A, Alvarez-Jaimes L, Sanchez-Vera I, Giuffrida A, Serrano A, Baixeras E, Navarro M, Parsons LH, Piomelli D, Rodriguez de Fonseca F. Regulation of brain anandamide by acute administration of ethanol. Biochem J. (2007, in press) Hardison S., Weintraub S, Giuffrida A. Quantification of endocannabinoids in rat biological samples by GC/MS: technical and theoretical considerations. Prostagland. Lipid Mediators 81: (2006). Giuffrida A., Price D.A., Daws L.C., Owens W.A., Gould G.G., Frazer A., Seillier A., Roberts J.L.. Inhibition of dopamine transporter activity by cannabinoids. Neuropsychopharmacology, 30: S133 (2005). Solbrig M.V., Adrian R., Baratta J., Piomelli D., Giuffrida A. A role for endocannabinoids in viral-induced dyskinetic and convulsive phenomena. Exp. Neurol. 194: (2005). Giuffrida A., Leweke F.M., Gerth C.W., Fegley, D., Faulhaber, J., Klosterkoetter J., Valino F., Piomelli D. Elevated anandamide levels negatively correlate with psychotic symptoms of acute schizophrenia. Neuropsycopharmacology 29: (2004). Sparling, P.B., Giuffrida A., Piomelli D., Rosskopf L., Dietrich A. Exercise activates the endocannabinoid system. Neuroreport 14: (2003). Ferrer B., Asbrock N., Kathuria S., Piomelli D., Giuffrida A. Effects of levodopa on endocannabinoid signaling in the basal ganglia: implications for the treatment of levodopa-induced dyskinesias. Eur. J. Neurosci. 18: (2003). Schaebitz W.R., Giuffrida A., Berger G., Aschoff A., Schwaninger M., Schwab S., Piomelli D. Release of fatty acid amides in a patient with hemispheric stroke. Stroke 33: (2002). Giuffrida A., Beltramo M., Piomelli D. Mechanisms of endocannabinoid inactivation: biochemistry and pharmacology. J. Pharmacol. Exp. Ther. 298: 7-14 (2001). Giuffrida A., Rodriguez de Fonseca F., Nava F., Loubet-Lescoulie P., Piomelli D. Elevated circulating levels of anandamide after administration of the transport inhibitor, AM404. Eur. J. Pharmacol. 408: (2000). Calignano A., Katona I., Desarnaud F., Giuffrida A., La Rana G., Mackie K., Freund T.F., Piomelli D. Bidirectional control of airway responsiveness by endogenous cannabinoids. Nature, 408: (2000). 56

57 Giuffrida A., Rodriguez de Fonseca F., Piomelli D. Quantification of bioactive acylethanolamides in rat plasma by electrospray mass spectrometry. Anal. Biochem. 280: (2000). Beltramo M., Rodriguez de Fonseca F., Navarro M., Calignano A., Gorriti M.A., Grammatikopoulos G., Sadile A.G., Giuffrida A., Piomelli D. reversal of dopamine D2- receptor responses by an anandamide transport inhibitor. J. Neurosci. 20: (2000). Giuffrida A., Parsons L.H., Kerr T.M., Rodriguéz de Fonseca F., Navarro M., Piomelli D. Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nature Neuroscience 2: (1999). Calignano A., La Rana G., Giuffrida A., Piomelli D. - Control of pain initiation by endogenous cannabinoids. Nature, 394: (1998). Ken M. Hargreaves Professor and Chair of Endodontics Professor of Pharmacology and Physiology D.D.S., Georgetown University Ph.D., Uniformed Services University of the Health Sciences Office: (210) hargreaves@uthscsa.edu My primary research interests are in the pharmacology of pain and inflammation. A major focus is on pharmacological regulation of unmyelinated "C" fiber nociceptors, as well as their plasticity in response to inflammation or nerve injury. Investigations are in progress evaluating the effects of cannabinoids, opioids, adrenergics, NPY, sex steroids and other drugs on regulating the activity of these fibers. In addition, we are interested in identifying major classes of inflammatory mediators and associated receptor/signal transduction systems which mediate activation, sensitization and phenotypic plasticity of these primary afferent fibers in response to tissue inflammation. Responses are measured using isolated superfused tissue, primary trigeminal cultures, microdialysis probes implanted in situ, RIA, EIA, real time PCR, Affymetrex analyses, IHC, ISH, confocal microscopy, behavior, etc. Selected Publications Akopian A, Ruparel N, Jeske N, Hargreaves KM. TRPA1 desensitization in sensory neurons is agonist-dependent and regulated by TRPV1-directed internalization. J Physiol (Lond.) (in press) Ruparel N, Patwardhan A, Akopian A, Hargreaves KM. Homologous and heterologous desensitization of capsaicin and mustard oil responses utilize different cellular pathways in nociceptors. Pain (in press)

58 Berg K, Patwardhan A, Sanchez T, Silva Y, Hargreaves KM, Clarke W. Rapid regulation of Mu opiod receptor signaling in primary sensory neurons. J Pharmacol Expt Therap 321:839, Gibbs J, Diogenes A, Hargreaves KM. Neuropeptide Y modulates effects of bradykinin and prostaglandin E2 on trigeminal nociceptors via activation of the Y1 and Y2 receptors. Br J Pharmacol 150:72-9, Berg K, Zardeneta G, Hargreaves KM, Clarke W, Milam S. Integrins regulate opioid receptor signaling in trigeminal ganglion neurons. Neuroscience 144:889-95, Diogenes A, Akopian A, Hargreaves KM. NGF Upregulates TRPA1. J Dent Res 86:550-5, Patwardhan A, Jeske N, Price T, Gamper N, Akopian A, Hargreaves KM. The cannabinoid WIN inhibits TRPV1 responses and evokes peripheral antihyperalgesia/antinociception via activation of the calcineurin pathway. Proc Natl Acad Sci USA 103: , Jeske N, Patwardhan A, Gamper N, Price T, Akopian A, Hargreaves KM. Cannabinoid Win 55,212-2 regulates TRPV1 phosphorylation in sensory neurons. J Biol Chem 281(43): , Diogenes A, Patwardhan A, Jeske N, Ruparel N, Goffin V, Akopian A, Hargreaves KM. Prolactin Modulates TRPV1 in Female Rat Trigeminal Sensory Neurons. J. Neuroscience 26: , Patwardhan A, Diogenes A, Berg K, Fehrenbacher J, Clarke W, Akopian A, Hargreaves KM. PAR-2 agonists activate trigeminal nociceptors and induce functional competence in the Delta opioid receptor. Pain 125:114-24, Price T, Hargreaves KM and Cevero F. Protein expression and mrna cellular distribution of the NKCC1 co-transporter in the dorsal root and trigeminal ganglia of the rat. Brain Res 1112:146-58, Price T, Flores C, Hargreaves KM. The RNA binding and transport proteins staufen and fragile X mental retardation protein are expressed by rat primary afferent neurons and localize to preipheral and central axons. Neuroscience 141: , Gibbs J, Flores C, and Hargreaves KM. Attenuation of capsaicin-evoked mechanical allodynia by peripheral neuropeptide Y Y 1 receptors. Pain 124:167-74, Wadachi R and Hargreaves KM. Trigeminal Nociceptors Express TLR-4 and CD14. A Mechanism for Pain due to Infection. J Dent Res 85:49-52, Bowles W, Hargreaves KM. Chronic Nerve Growth Factor Administration Increases the Peripheral Exocytotic Activity of Capsaicin-Sensitive Cutaneous Neurons. Neurosci Lett 403:305-8,

59 Patwardhan A, Berg K, Akopian A, Jeske N, Gamper N, Clarke W, and Hargreaves KM. Bradykinin induced functional competence and trafficking of the delta opioid receptor in trigeminal nociceptors. J Neurosci 25: , Price TJ, Jeske N, Flores CM, Hargreaves KM. Pharmacological interactions between calcium/calmodulin-dependent kinase II α and TRPV1 receptors in rat trigeminal sensory neurons. Neurosci Lett 389:94-8, Price TJ, Patwardhan AM, Flores CM, Hargreaves KM. A role for the anandamide membrane transporter in TRPV1 mediated neurosecretion from trigeminal nociceptors. Neuropharmacol. 49:25-39, Price TJ, Louria MD, Candelario-Soto D, Dussor GO, Jeske NA, Patwardhan AM, Diogenes A, Trott AA, Hargreaves KM, Flores CM. Treatment of trigeminal ganglion neurons in vitro with NGF, GDNF, and BDNF: effects on neuronal survival, neurochemical properties and TRPV1-mediated neuropeptide secretion. BMC Neurosci Jan 24;6(1):4. Gibbs J, Flores C, Hargreaves KM. NPY inhibits capsaicin-sensitive nociceptors via a Y1 receptor mediated mechanism. Neuroscience 125:703-9, Price T, Patwardhan A, Akopian A, Hargreaves K, Flores, C. Cannabinoid receptor independent actions of the aminoalkylindole cannabinoid Win on trigeminal sensory neurons. Br J Pharmacol 142:257-66, Price T, Patwardhan A, Akopian A, Hargreaves K, Flores C. Modulation of trigeminal sensory neurons by the dual cannabinoid-vanilloid agonists anandamide (AEA), N- arachidonyl-dopamine (NADA) and arachdonyl-2-chloroethylamide (ACEA). Br J Pharmacol 141: , Dussor G, Helesic G, Hargreaves K, Flores C. Cholinergic modulation of nociceptive responses in vivo and neuropeptide release in vitro at the level of the primary sensory neuron. Pain 107:22-31, Dussor GO. Leong AS. Gracia NB. Kilo S. Price TJ. Hargreaves KM. Flores CM. Potentiation of evoked calcitonin gene-related peptide release from oral mucosa: a potential basis for the pro-inflammatory effects of nicotine. European Journal of Neuroscience. 18(9): , Bowles WR, Flores CM, Jackson DL, Hargreaves KM. α-adrenoceptor regulation of CGRP release from capsaicin-sensitive neurons. J Dent Res 82: , Hargreaves KM, Bowles WR, Jackson DL. Intrinsic regulation of icgrp release from dental pulp sympathetic fibers. J Dent Res 82:398, Price T, Helesic G, Parghi D, Hargreaves KM, Flores C. The neuronal distribution of cannabinoid receptor type one in the trigeminal ganglion of the rat. Neuroscience 120:155-62,

60 Dussor G, Leong A, Gracia N, Kilo S, Price T, Hargreaves, KM, Flores C. A cellular and molecular basis for the pro-inflammatory effects of nicotine: potentiation of capsaicinevoked CGRP release from oral mucosal. Eur J Neurosci 18: , George Henderson Professor of Medicine and Pharmacology Ph.D., Vanderbilt University Office: (210) hendersong@uthscsa.edu The primary objective of my research is to gain a better understanding of the basic mechanisms underlying alcohol and oxidative stress-induced damage to the developing brain. The pro-oxidant effects of ethanol have been documented in adult and fetal tissues (brain and liver) using in vivo models and in primary cultures of fetal rat cortical neurons and neonatal rat cortical astrocytes. Current studies are focusing on the accelerated apoptotic death of neurons exposed to alcohol with mitochondria as the source of reactive oxygen species and astrocyte-mediated protection from this apoptotic death. Findings in our laboratory have illustrated that the well-documented increase in neuron death in the ethanol-exposed developing brain may be due to enhanced mitochondrially-mediated apoptosis (intrinsic pathways). Confocal and multiphoton imaging of live fetal cortical neurons have illustrated that ethanol can elicit an increase in reactive oxygen species within only minutes of exposure and that this is associated with decreased levels of the antioxidant, glutathione. New findings illustrate that astrocytes provide protection against this oxidative stress-induced apoptotic death by maintaining neuron glutathione homeostasis. The system that provides this neuroprotection can be up-regulated at, at least four points, each of which is mediated by an "antioxidant response element"(are). This transcriptional-level regulation can be manipulated and studies are ongoing to adapt this to controlled neuroprotection. In summary, current studies address oxidative stress-mediated apoptotic neuron death in the developing brain, the role of glutathione antioxidant systems in protection against this, and the glia-mediated neuroprotection. Selected Publications Rathinam ML, Watts LT, Stark AA, Mahimaimathan L, Stewart J, Schenker S, Henderson GI. Astrocyte control of fetal cortical neuron glutathione homeostasis: Upregulation by ethanol. J. Neurochem. 96: , Watts LT, Rathinam ML, Schenker S, Henderson GI. Astrocytes protect neurons from ethanol-induced oxidative stress and apoptotic death. J Neurosci Res. 80: , Ramachandran V, Watt LT, Maffi S, Chen JJ, Schenker S, Henderson GI. Ethanol- Induced Oxidative Stress Precedes Mitochondrially-Mediated Apoptotic Death of Cultured Fetal Cortical Neurons. J Neuroscience Research V74: ,

61 Musatov A, Carroll C, Liu YC, Henderson G, Weintraub S, Robinson N. Identification of Bovine Heart Cytochrome c Oxidase Subunits Modified by the Lipid Peroxidation Product 4-Hydroxy-2-Nonenal. Biochemistry 41: , Ramachandran V, Perez A, Chen JJ, Senthil D, Schenker S, Henderson GI. In Utero Ethanol Exposure Caused Mitochondrial Dysfunction Which Can Result in Apoptotic Cell Death In Fetal Brain: A Potential Role for 4-Hydroxynonenal. Alcohol Clin Exp Res 25: , Julie G. Hensler Associate Professor of Pharmacology Ph.D., Northwestern University Office: (210) hensler@uthscsa.edu I am interested in the cellular and molecular mechanisms by which neurotransmitter receptor systems compensate or change in disease states (e.g. major depressive disorder, alcoholism) or in response to repeated drug treatment. Because the treatment of many psychiatric disorders involves long-term pharmacological intervention, compensatory changes in the sensitivity of central receptor systems may be involved in the mechanism by which drugs produce their therapeutic or side effects. I have focused my research primarily on the regulation of serotonin receptor function. To date there have been identified some fourteen subtypes of receptor for serotonin which are targets for a wide variety of drugs (e.g. hallucinogens, and drugs used to treat schizophrenia, anxiety, migraine). Serotonergic neurotransmission is altered by several classes of antidepressant drugs as well. In my laboratory we have taken both in vivo and in vitro approaches to examine the processes underlying the regulation of serotonin receptor function and expression. In vitro systems (i.e. cells in culture) allow us to examine the regulation of serotonin receptors in more mechanistic studies. Cell lines, which have been transfected to express serotonin receptor subtypes, as well as cell lines which endogenously express these receptors, are used. Our findings from these studies are compared to what has been observed to occur in the brain. We utilize molecular probes (e.g. antibodies, dominant negative mutants, antisense oligonucleotides) to examine the cellular processes by which serotonin receptor function is regulated. Receptor function is assessed using biochemical, physiological and behavioral assays. We are currently utilizing [35S]GTPgammaS autoradiography to investigate the regulation of serotonin- 1A receptor function at the level of receptor-g protein interaction in discrete brain regions following administration of psychoactive drugs such as antidepressants. These studies may further our understanding of the regulation of serotonin receptor function, and may have impact on our understanding of the regulation of G-protein coupled receptors as a superfamily. The serotonergic system in brain has been implicated in substance abuse and addiction, as well as many psychiatric disorders. We have begun studies to identify differences in serotonin receptors and in the serotonin transporter in genetically modified mice, which may prove useful models in which to examine the role of the serotonin system in alcohol and drug abuse, as well as affective disorders. For 61

62 example, we are interested in examining in mice deficient in brain-derived neurotrophic factor (BDNF) the neurochemical and behavioral effects of decreases in BDNF expression, the interaction of stress with this BDNF deficiency, as well as neurobiological changes in the serotonergic system that underlie alcohol preference, and depression. Selected Publications Hensler, J.G., Advani, T., Monteggia, L.M. Regulation of 5-HT1A receptor function in inducible BDNF knock-out mice following administration of corticosterone. Biol. Psychiatry 2007 Mar; [Epub ahead of print] Daws, L.C., Munn, J.L., Valdez, M.F., Frosto-Burke, T. Hensler, J.G. Serotonin Transporter Function, but not expression, is dependent on Brain Derived Neurotrophic Factor (BDNF): In Vivo Studies in BDNF-deficient Mice. J. Neurochem. Jan 24, 2007 [Epub ahead of print]. Advani, T., Hensler, J.G. Koek, W. Effect of early rearing conditions on alcohol drinking and 5-HT1A receptor function in C57BL/6 mice. Int. J. Neuropsychopharmacol Nov 30:1-13 [Epub ahead of print]. Hensler, J.G. Serotonergic Modulation of the Limbic System. Neuroscience and Behavioral Reviews 30: , Rossi D.V., Valdez M., Gould G.G., and Hensler J.G. Chronic administration of venlafaxine fails to attenuate 5-HT 1A receptor function at the level of receptor-g protein interaction. Int J. Neuropsychopharmacol. 8:1-14, Hensler J.G., Hodge C.W., and Overstreet D.H.: Reduced 5-HT 3 receptor binding and lower baseline plus maze anxiety in the alcohol-preferring inbred fawn-hooded rat. Pharmacol Biochem Behavior 77: , N.R. Sullivan, T. Burke, A. Siafaka-Kapadai, Javors, M. and Hensler, J.G.: Effect of valproic acid on 5-HT 2A receptor signaling in C6 glioma cells. J. Neurochem. 90: , Hensler J.G.: Regulation of 5-HT 1A receptor function in brain following agonist or antidepressant administration. Life Sciences 72: , Hensler J.G., Ladenheim E.E. and Lyons W.E: Ethanol consumption and serotonin-1a (5-HT 1A ) receptor function in heterozygous BDNF (+/-) mice. J. Neurochem. 85: , Valdez M., Burke T.F. and Hensler J.G.: Selective heterologous regulation of 5-HT 1A receptor-stimulated [ 35 S]GTPγS binding in the anterior cingulate cortex as a result of 5- HT 2 receptor activation. Brain Research 957: , Hensler J.G. Differential regulation of 5-HT 1A receptor-g protein interactions in brain following chronic antidepressant administration. Neuropsychopharmacology 26: ,

63 Hanley N.R. and Hensler J.G.: Mechanisms of ligand-induced desensitization of the 5- HT 2A receptor. J. Pharmacol. Exp. Ther. 300: , Anji A., Sullivan Hanley N.R., and Hensler J.G.: The role of PKC in the regulation of serotonin2a (5-HT 2A ) receptor expression. J Neurochem. 77: , Hensler J.G. and Durgam H.: Regulation of 5-HT 1A receptor-stimulated [ 35 S]GTPγS binding as measured by quantitative autoradiography following chronic agonist administration. Brit. J. Pharmacol. 132: , Scalzitti J.M. and Hensler J.G. The design and efficacy of a serotonin-2a receptor Antisense oligodeoxynucleotide. In: Methods in Enzymology, Antisense Techniques, M.I. Phillips (ed), pp 76-89, Academic Press, Hensler J.G., Cervera, L.S., Miller H.A. and Corbitt J.: Expression and modulation of 5- HT 1A receptors in P11 cells. J. Pharmacol. Exp. Therap. 278: , Carmen Hinojosa-Laborde Associate Research Professor of Anesthesiology and Pharmacology Ph.D., UT Health Science Center, San Antonio Office: (210) laborde@uthscsa.edu The mechanisms of post-menopausal hypertension are not well understood and few animal models exist to study this phenomenon. In my laboratory, we use the Dahl Salt Sensitive rat as an animal model of post-menopausal hypertension to investigate the mechanisms responsible for the hypertension. The Dahl Salt Sensitive rat shares the common trait of salt-sensitivity with many post-menopausal hypertensive women. While many observations implicate a role for estrogen, the effects of aging on the regulation of blood pressure can also contribute to the development of salt-sensitive hypertension in postmenopausal women. My research focuses on understanding how estrogen loss, aging and salt diet can result in the activation of pressor systems important in the development of hypertension. Two major controllers of blood pressure are the sympathetic nervous system and the renin angiotensin system. My studies are designed to determine how estrogen loss, aging and salt diet can alter the ability of the sympathetic nervous system and the renin angiotensin system to control blood pressure. In our experiments, we record blood pressure and heart rate by radiotelemetry to determine the long-term effects of aging and estrogen loss in female rats when they are fed a low salt diet and a high salt diet. We assess the contribution of the sympathetic nervous system by recording sympathetic nerve activity, measuring circulating catecholamines, and by various pharmacological techniques. The contribution of the renin-angiotension system assessed by measuring circulating levels of various components of the renin angiotensin system, and by pharmacologically blocking 63

64 angiontensin receptors in the blood vessels. Molecular mechanisms of the regulation of the renin-angiotensin system are also determined. Selected Publications Hinojosa-Laborde C, Mifflin SW: Sex Differences in Blood Pressure Response to Intermittent Hypoxia in Rats. Hypertension, 46: , Oct Hinojosa-Laborde C, Craig T, Zheng W, Ji H, Haywood J, and Sandberg K: Ovariectomy Augments Hypertension in Aging Female Dahl Salt-Sensitive Rats. Hypertension 44: , Maric C, K. Sandberg, and C. Hinojosa-Laborde: Glomerulosclerosis and Tubulointerstitial Fibrosis are Attenuated with 17ß-Estradiol in the Aging Dahl Salt Sensitive Rat. Journal of the American Society of Nephrology, 15(6): , Hinojosa-Laborde C, Lange DL, Haywood JR. Role of female sex hormones in the development and reversal of dahl hypertension. Hypertension. Jan;35(1 Pt 2):484-9, Lange DL, Haywood JR, Hinojosa-Laborde C. Endothelin enhances and inhibits adrenal catecholamine release in deoxycorticosterone acetate-salt hypertensive rats. Hypertension. Jan;35(1 Pt 2):385-90, Hinojosa-Laborde, C., I. Chapa, D. Lange and J.R. Haywood. Gender Differences in sympathetic nervous system regulation. Clin. & Exp. Pharmacol. & Physiol. 26: , Haywood, J.R. and Hinojosa-Laborde, C. Sexual dimorphism of sodium-sensitive renal wrap hypertension. Hypertension 30: , Syed Imam Assistant Professor of Medicine and Pharmacology Ph.D., Hamdard University (India) & US FDA/NCTR (Jefferson, AR) Office: (210) The main research goal of my laboratory is to understand the molecular basis of neurodegeneration, which can be implicated to develop therapeutic trials for neurodegenerative diseases. The broad areas of investigation in my lab include the study of the molecular mechanisms of neuronal cell death, novel cell death and cell survival pathways and their correlation with the molecular basis of Parkinson's disease (PD), α-synucleinopathies and related neurodegenerative disorders. We strive to identify regulatable targets that can be manipulated by chemical or genetic means for pharmaceutical and therapeutic intervention. 64

65 Presently, my laboratory is focused on role of signaling kinases in the regulation of various components of PD as a therapeutic target in animal models and in PD patients. Our novel finding that oxidative stress sensitive tyrosine kinase renders parkin, an E3 ubiquitin ligase, non-functional has opened up various new avenues to understand progression of nigro-striatal degeneration during the pathogenesis of PD. We are investigating the role of cell signaling regulation of α-synuclein and LRRK2 in the pathogenesis of PD. Furthermore, we have ongoing pre-clinical studies on the role of kinase inhibitors as a potential therapeutic approach in slowing down the progression of PD. In addition, we are working to develop projects on molecular signaling mechanisms during progression of AD. Furthermore, my laboratory has a very strong background in the oxidative-stress mediated neurotoxicity induced by substituted amphetamines as well as in DNA damage and repair in aging brain. My laboratory has set-up extensive collaborations with various PD research and clinical centers in USA and Europe that include Morris Udall Center of Excellence for PD Research at Johns Hopkins School of Medicine, Department of Neurology at UCSD, Hertie Institute of Clinical Brain Research at University of Tubingen, Germany and Brain Mind Institute of Swiss Federal Institute of Technology, Switzerland. Unique technical and clinical research capabilities/instrumentation in my laboratory include Gene and Protein Interaction, Cell-Signaling Studies, Biochemical and Immunochemical analysis, HPLC analysis of neurochemicals and pro-oxidants, Genesilencing and overexpression using plasmid, lenti- and retro-viral vectors, protein purification, kinomics, analysis of proteome and transciptome, primary and permanent neuronal cultures, animal modeling of neurodegenerative disorders, analysis of postmortem human brain samples. Immunoprecipitation, gene-transfection, Western blots, etc. Selected Publications Selected from 32 peer-reviewed publications or submitted manuscripts. Imam SZ, Sriram SR, Liao X, Ko HS, Savitt JM, Zhou Q, Pearson DW, Yamamoto A, Valente AJ, Andres-Mateos E, Trinkaus DB, Schools SE, Pletnikova O, Troncoso JC, Ali SF, Bains MC, Roberts JL, Kahle PJ, Dawson VL, Clark RA, Li S, Dawson TM. Inhibition of Parkin's E3 Ubiquitin Ligase Activity Through c-abl mediated Tyrosine Phosphorylation: Implications for Parkinson's Disease. Nature Medicine (final submission). Imam SZ, Indig FE, Cheng WH, Saxena SP, Stevnsner T, Kufe D, Bohr VA. (2007) Cockayne syndrome protein B interacts with and is phosphorylated by c-abl tyrosine kinase. Nucleic Acids Research (in press). Wong HK, Muftuoglu M, Beck G, Imam SZ, Bohr VA, Wilson DM III. (2007) Cockayne syndrome B protein stimulates apurinic endonuclease 1 activity and protects against agents that introduce base excision repair intermediates. Nucleic Acids Research 35(12):

66 Imam SZ, Jankovic J, Ali SF, Skinner JT, Xie W, Conneely OM, Le WD. (2005) Nitric oxide mediates increased susceptibility to dopaminergic damage in Nurr1 heterozygous mice. FASEB J 19(11): Imam SZ, Karahalil B, Hogue BA, Souza-Pinto NC, Bohr VA. (July 2005) Mitochondrial and nuclear DNA-repair capacity of various brain regions in mouse is altered in an agedependent manner. Neurobiol Aging. He Y, Imam SZ, Dong Z, Jankovic J, Ali SF, Appel SH, Le W. (2003) Role of nitric oxide in rotenone-induced nigro-striatal injury. J Neurochem 86(6): Imam SZ, Ali SF. (2001) Aging increases the susceptibility to methamphetamineinduced dopaminergic neurotoxicity in rats: Correlation with peroxynitrite production and hyperthermia. J Neurochem 78(5): Imam SZ, Newport GD, Itzhak Y, Cadet JL, Islam F, Slikker W, Ali SF. (2001) Peroxynitrite plays a role in methamphetamine-induced dopaminergic neurotoxicity: Evidence from mice lacking neuronal nitric oxide synthase gene or overexpressing copper-zinc superoxide dismutase. J Neurochem 76(3): Imam SZ, Islam F, Itzhak Y, Slikker W, Ali SF. (2000) Prevention of dopaminergic neurotoxicity by targeting nitric oxide and peroxynitrite: Implications for the prevention of methamphetamine-induced neurotoxic damage. Ann NY Acad Sci 914: Imam SZ, Ali SF. (2000) Selenium, an antioxidant, attenuates methamphetamineinduced dopaminergic toxicity and peroxynitrite generation. Brain Res 855(1): Imam SZ, Crow JP, Newport GD, Islam F, Slikker W, Ali SF. (1999) Methamphetamine generates peroxynitrite and produces dopaminergic neurotoxicity in mice: Protective effects of peroxynitrite decomposition catalyst. Brain Res 837(1-2): Yu X, Imam SZ, Newport GD, Slikker W, Ali SF. (1999) Ibogaine blocked methamphetamine-induced hyperthermia and induction of heat shock protein in mice. Brain Res 823(1-2): Imam SZ, Newport GD, Islam F, Slikker W, Ali SF. (1999) Selenium, an antioxidant, protects against methamphetamine-induced dopaminergic neurotoxicity. Brain Res 818(2): Wouter Koek Associate Professor of Psychiatry and Psychology Ph.D., University of Utrecht, The Netherlands Phone: (210) koek@uthscsa.edu Dr. Koek s laboratory uses animal models aimed at aiding the development of medications for substance abuse. The models involve behavioral effects that range from 66

67 directly observable (e.g., drug-induced motor impairment) to effects examined by operant conditioning procedures (e.g., discriminative stimulus effects, which are related to subjective drug effects in humans). The models are used mainly to examine the effects of alcohol and the club drug gamma-hydroxybutyrate (GHB), because alcohol abuse is a major public health problem, and because recreational use of GHB is increasing dramatically. One of the difficulties with treating alcohol abuse is that alcoholism is not a homogeneous disease entity. The laboratory focuses on early onset alcoholism, the subtype posing the most severe problems. Early onset alcoholism is often associated with poor inhibitory control, evidenced by increased impulsivity and aggression, that is exacerbated further by an increased sensitivity to the activating, disinhibiting effects of alcohol and by a decreased sensitivity to its motor impairing effects. These features, which result from interactions of genetic and environmental factors, involve decreased serotonin levels, increased neurosteroid levels, and altered functioning of GABA-ergic systems. Increased understanding of these underlying mechanisms will contribute to better treatment efforts. The pharmacological mechanisms by which GHB produces its abuse-related effects are poorly understood. GHB abuse is likely related to its subjective effects, and subjective effects of drugs in humans can often be predicted from drug discrimination experiments in animals. The discriminative stimulus effects of GHB are likely to involve several different receptor mechanisms. Some of these mechanisms may be unique to GHB (i.e., those involving specific GHB receptors), whereas others may be in common with other compounds (i.e., those involving GABAA and GABAB receptors). The laboratory examines the involvement of these mechanisms in the discriminative stimulus effects of GHB under various conditions (e.g., training dose, alternative training condition). By identifying the role of specific receptors in abuse-related effects of GHB, future studies may be better able to develop specific, pharmacologically targeted therapies for GHB abuse. Selected Publications Koek W, Chen W, Mercer SL, Coop A, France CP. Discriminative stimulus effects of gamma-hydroxybutyrate: role of training dose. J Pharmacol Exp Ther 317:409-17, Koek W, Carter LP, Lamb RJ, Chen W, Wu H, Coop A, France CP. Discriminative stimulus effects of gamma-hydroxybutyrate (GHB) in rats discriminating GHB from baclofen and diazepam. J Pharmacol Exp Ther 314:170-9, 2005, Bergman J, France CP, Holtzman SG, Katz JL, Koek W, Stephens DN. Agonist efficacy, drug dependence, and medications development: preclinical evaluation of opioid, dopaminergic, and GABAA-ergic ligands. Psychopharmacology 153:67-84,

68 Y.W. Francis Lam Associate Professor of Pharmacology and Medicine Clinical Associate Professor & James O. Burke Endowed Centennial Fellow in Pharmacy at the Univ. of Texas at Austin Pharm.D., University of Minnesota Office: (210) Variability in pharmacologic response to a drug can be partially related to interindividual differences in pharmacokinetics, which can be modulated by an individual's metabolic capacity and concomitant therapy. Development and availability of different in vitro systems over the years have allowed for identification of major cytochrome P-450 isoenzymes and assessment of enzyme inhibition potentials. My primary research interest is on the pharmacodynamic and pharmacokinetic consequences of cytochrome P-450 isoenzymes-mediated drug metabolism. In vivo probes of different isoenzymes are used to investigate the intrinsic and extrinsic variants affecting metabolic capacity, and to investigate the therapeutic utility of metabolic profiling. These probes also allow an opportunity to further address possible genetic and environmental determinants of drug responsiveness among different ethnic groups. Selected Publications Friedberg SJ, Lam YWF, Blum JJ, Gregerman RL. Insulin absorption: a major factor in apparent insulin resistance and the control of type 2 diabetes mellitus. Metabolism 2006; 55: Johnson BA, Javors MA, Lam YWF, Wells LT, Tiouririne M, Roache JD, Ait-Daoud N, Lawson K. Kinetic and cardiovascular comparison of sustained-release and immediaterelease isradipine among healthy volunteers. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: Lam YWF, Javors M, Ait-Daoud N, Roach J, Johnson BA. Relative bioavailability of ondansetron solution versus expemporaneous gelatin capsule formulation containing crushed tablets. Pharmacotherapy 2004; 24: Lam YWF, Alfaro CL, Ereshefsky L, Miller M. Pharmacokinetic and pharmacodynamic interactions of oral midazolam with ketoconazole, fluoxetine, fluvoxamine, and nefazodone. J Clin Pharmacol 43: , Shirley KL, Hon YY, Penzak SR, Lam YWF, Spratlin V, Jann MW. Correlation of cytochrome P450 (CYP)1A2 activity using caffeine phenotyping and olanzapine disposition in healthy volunteers. Neuropsychopharmacology 28: , Lam Y.W.F, Gaedigk A, Ereshefsky L, Alfaro C, Simpson J. CYP2D6 inhibition by SSRIs: Analysis of achievable plasma concentrations and the effect of ultra-rapid metabolism at CYP2D6. Pharmacotherapy 22:1001-6,

69 Alfaro CL, Lam YWF, Simpson J, Ereshefsky L. CYP2D6 status of extensive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, or sertraline. J Clin Psychopharmacology 19: , Lam, Y.W.F, Jann, M.W., Chang, W.H., Yu, H.S., Lin, S.K., Chen, H. and Davis, C.M. Intra- and inter-ethnic variability in reduced haloperidol to haloperidol ratio. J. Clin Pharmacol 35: , Lam Y.W.F., Chang WH, Jann MW, Chen H. Variabilities in haloperidol interconversion and the reduced haloperidol / haloperidol ratio. Neuropsychopharmacology 7:33-39, Richard Lamb Associate Professor of Psychiatry and Pharmacology Ph.D., University of Arkansas for Medical Science Office: (210) lamb@uthscsa.edu Many drugs have important behavioral actions. One such behavioral action is drug addiction. Drug addiction results from the interactions between an individuals ongoing and past behavior and the pharmacological actions of a drug. The behavioral pharmacology of drug addiction aims at understanding these interactions. Thus, behavioral pharmacology aims to understand how drugs affect behavior, understand how behavior affects drug action, and understand the pharmacological mechanism of these actions. Developing these understandings is fundamental to understanding the behavioral biology of drug addiction and to developing new and more effective treatments of drug addiction. Ongoing studies address this both from a treatment development perspective and from a basic science perspective. Frequently, however, research is conducted that combines these two perspectives. Two examples of how these perspectives are combined are ongoing studies on the effects of serotonin re-uptake inhibitors on ethanol selfadministration in rats and ongoing studies on shaping abstinence in smokers. Selected Publications Jarbe TU, Lamb RJ, Lin S, Makriyannis A. (R)-methanandamide and Delta 9-THC as discriminative stimuli in rats: tests with the cannabinoid antagonist SR and the endogenous ligand anandamide. Psychopharmacology (Berl) Aug;156(4): Lamb RJ, Jarbe TU. Effects of fluvoxamine on ethanol-reinforced behavior in the rat. J Pharmacol Exp Ther Jun;297(3):

70 Lamb RJ, Järbe, TUC, Makriyannis A, Lin S, and Goutopoulos A, Effects of 9- tetrahydrocannabinol, (R)-methanandamide, SR , and d-amphetamine before and during daily 9-tetrahydrocannabinol dosing. European Journal of Pharmacology 398: , Järbe, TUC, Lamb, RJ, Lin, S, Makriyannis, A. 9-THC training dose as a determinant for (R)-methanandamide generalization in rats: A systematic replication Behavioral Pharmacology 11(1):81-86, Senlin Li Associate Professor of Medicine and Pharmacology M.D., University of Geneva Office: (210) lis1@uthscsa.edu My primary research interest is to develop autologous hematopoietic stem cell (HSC) gene therapy, particularly HSC-derived macrophage gene therapy for neurodegenerative diseases, atherosclerosis and other inherited blood disorders. Macrophages are recruited from bone marrow to most tissues of the body, including the central nervous system, thus making them an attractive option to deliver therapeutic genes. In macrophage-mediated gene therapy, HSCs will be mobilized from bone marrow, isolated by apheresis, and transduced ex vivo to establish stable expression of therapeutic genes. The transduced HSCs are given back to the same patients and thereafter graft will form various lineages of blood cells, including macrophages. Because they are under the control of macrophage-specific promoters, the therapeutic genes will be expressed at high levels of macrophages only. Neurotrophic factors can be beneficial to degenerative neurons, such as glial cell-derived neurotrophic factor (GDNF) to Parkinson's disease (PD) and nerve growth factor (NGF) to Alzheimer's disease (AD). Over-expression of apoe, apoai, LXR (liver X receptor), etc. in macrophages has been shown to ameliorate atherosclerosis. These projects capitalize on the super-macrophage promoters that we have recently developed and lentiviral vectors that are superior in transduction of HSCs while maintaining their stem cell nature. Recent advance in stem cell research has demonstrated the feasibility to produce patient-specific ES cells by nuclear transfer (ntes). Mouse ES cells have been differentiated in vitro into HSCs that can rescue leathally-irradiated syngeneic recipients. HSCs created by nuclear transfer can give old animals youthful blood cells. Taken together, ntes cells can be coaxed in vitro to HSCs that will rejuvenate the blood. Those HSCs will be the best carrier of the gene therapy described above. Other ongoing projects in Dr. Li's laboratory include transcriptional regulation of PDrelated genes, genome-wide mapping of histone acetylation in cancer cells, age-related 70

71 oxidative DNA damage and repair, and cellular mechanism of parkin in neurodegenerative diseases. Selected Publications Imam SZ, Sriram SR, Liao X, Zhou Q, Yamamoto A, Valente AJ, Ko HS, Pletnikova O, Troncoso JC, Ali SF, Kahle PJ, Dawson VL, Clark RA, Dawson TM, Li S. Inhibition of Parkin s E3 Ubiquitin Ligase Activity Through c-abl-mediated Tyrosine Phosphorylation: Implications for Parkinson s Disease. Revised to Nature Medicine He, W, Qiang M, Ma W, Valente AJ, Quinones M, Wang W, Reddick, RL, Qifu X, Ahuja SS, Clark RA, Freeman GL, and Li S. Development of a synthetic promoter for macrophage gene therapy. Human Gene Therapy 11: , Zhao S, Venkatasubbarao K, Li S, Freeman JW. Requirement of a specific Sp1 site for HDAC-mediated repression of transforming growth factor bata type II receptor expression in human cancer cells. Cancer Research 63: , Li S, Valente AJ, and Clark RA. Multiple PU.1 binding is required for p40phox gene transcription in myeloid cells. Blood 99: , Li S, Valente AJ, Wang L, Gamez MJ, and Clark RA. Transcriptional regulation of the p67phox gene: Role of AP-1 in concert with myeloid-specific transcription factors. J Biol Chem 276: , Li S, Schlegel W, Valente AJ, and Clark RA. Critical flanking sequences of PU.1 binding sites in myeloid-specific promoters. J Biol Chem 274: , Feng Liu Professor of Pharmacology and Biochemistry Ph.D., Iowa State University Office: (210) liuf@uthscsa.edu Our primary interest lies in studying the insulin signal transduction pathway, which is activated when the hormone insulin binds to its cell surface receptors, resulting in a cascade of biochemical reactions that culminates in regulation of metabolic processes such as glucose uptake and glycogen synthesis. Defects in any of the steps along this signaling cascade can result in insulin resistance, one of the primary contributors to developing Type 2 diabetes. In order to better understand the molecular mechanism of insulin signal transduction and insulin resistance, we are using molecular biology, biochemistry, and cell biology approaches as well as animal models to identify and characterize signaling components involved in insulin receptor signaling processes. It is our hope that better understanding of the signaling components involved in mediating insulin signal transduction will generate information that may be contributed to the development of new therapeutic drugs for the treatment of Type 2 diabetes. 71

72 We are also interested in investigating the link between insulin signaling and aging. Recent studies from invertebrates suggested that reducing insulin/igf-1 signaling in the neurons can extend the life-span of these organisms. Whether reducing neuronal insulin/igf-1 signaling in mammals extends their life-span remains to be established. We are currently developing animal models in order to determine whether neuronal insulin signaling plays a role in regulating mammalian longevity and aging. Selected Publications Wang, L., Balas, B., Christ-Roberts, C.Y., Kim, R.Y., Ramos, F.J., Kikani, C.K., Li, C., Deng, C., Reyna, S., Musi, N., Dong, L.Q., DeFronzo, R.A., and Liu, F. (2007) Perpheral disruption of Grb10 gene enhances insulin signaling and sensitivity in vivo. Mol. Cell. Biol. In press. Wang C., Mao, X., Wang, L., Liu, M., Wetzel, M.D., Guan, K.-L., Dong, L.Q., and Liu, F. (2007) Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase-mediated serine phosphorylation of IRS-1. J. Biol Chem. 282: Li, J., Mao, X., Dong, L.Q., Liu, F., Tong, L. (2007) Crystal Structures of the BAR-PH and PTB Domains of Human APPL1. Structure 15: Riojas, R.A., Kikani, C.K., Wang, C., Mao, X., Zhou, L., Langlais, P.R., Hu, D., Roberts, J.L., Dong, L.Q., Liu, F. (2006) Fine-tuning PDK1 activity by phosphorylation at Ser163. J. Biol. Chem. 281: Mao, X., Langlais, P., Riojas, R.J., Wang, L., Ramos, F.J., Fang, Q., Christ-Roberts, C., Hong, J., Kim, R.Y., Kikani, C.K., Liu, F. Dong, L.Q. (2006) APPL1 binds to adiponectin receptors and mediates adiponectin signaling and function. Nat. Cell. Biol. 8: Ramos, F.J., Langlais, P., Hu, D., Dong, L.Q., and Liu, F. (2006) Grb 10-mediated degradation of the insulin receptor: A mechanism of negative regulation. Am. J. Physiol. Endocrinol. Metab. E Dong L.Q., Liu F. (2005) PDK2: The missing piece in the receptor tyrosine kinase signaling pathway puzzle. Am J Physiol Endocrinol Metab 289:E Kikani, C.K., Dong, L.Q., and Liu, F. (2005) "New"-clear functions of PDK1: Beyond a master kinase in the cytosol. J Cell. Biochem. 96, Langlais P., Wang C., Dong L.Q., Carroll C.A., Weintraub S.T., Liu F. (2005) Phosphorylation of Grb10 by mitogen-activated protein kinase: identification of Ser150 and Ser476 of human Grb 10zeta as major phosphorylation sites. Biochemistry 44: Lim M., Moon S. Y., Zheng Y., Wu H., Dong L.Q., and Liu F. (2004) Roles of PDK-1 and PKN in regulating cell migration and cortical actin formation of PTEN-deficient cells. Oncogene, 23,

73 Langlais P., Dong L.Q., Ramos F.J., Hu D., Li Y., Quon M.J., and Liu F. (2004) Negative Regulation of Insulin-Stimulated MAP Kinase Signaling By Grb10. Mol. Endocrinol. 18, Wick, K.R. Werner, E.D., Langlais, P., Ramos, F.J., Dong, L.Q., Shoelson, S.E., and Liu, F. (2003) Grb10 Inhibits Insulin-stimulated Phosphorylation of IRS-1/IRS-2 and Delays Akt Activation by Disrupting the Association of IRS-1/IRS-2 with the Insulin Receptor. J. Biol. Chem. 278, Wick, M.J., Wick, K. R., Dong, L.Q., and Liu, F. (2002) Autophosphorylation at Thr516 and Ser399 is important for the activity and function of 3-Phosphoinositide-dependent protein kinase-1 (PDK1). J. Biol. Chem. 277: Wick, M.J., and Dong, L.Q., Hu, D., Langlais, P., and Liu, F (2001) Insulin receptormediated p62dok tyrosine phosphorylation at Residues 362 and 398 plays distinct roles for binding GAP and Nck and is essential for inhibiting insulin-stimulated activation of Ras and Akt. J. Biol. Chem., 276, Dong, L.Q., Landa, L.R., Wick, M.J., Zhu, L., Mukai, H., Ono, Y. and Liu, F.. Phosphorylation of PKN by PDK1 mediates insulin signals to the actin cytoskeleton. Proc. Natl. Acad. Sci. USA. 97, , Xin-Yun Lu Assistant Professor of Pharmacology Ph.D., Washington State University Office: (210) lux3@uthscsa.edu Dr. Lu's major research interest concerns the molecular mechanisms and neural circuits underlying obesity, eating disorders, and depression. Current research focuses on the role of central melanocortin system and adiposity hormone leptin in the regulation of appetite, emotional and cognitive processing. Related research investigates functional interactions between the melanocortin system, leptin and the stress system using both acute stress challenges and chronic stress models of depression and eating disorders. More recent work examines neural mechanisms of leptin's antidepressant effects. Research strategies include conditional gene knockout mice, viral vector-mediated gene transfer, viral vector-mediated RNA interference, intra-nucleus microinjection, a variety of assays for behavioral changes, in vivo microdialysis, biochemical assays of protein phosphorylation, dual-labeling in situ hybridization and immunohistochemistry. Selected Publications X-Y Lu, CS Kim, A Frazer and W Zhang (2006). Leptin: a potential novel antidepressant. Proc Natl Acad Sci USA, 103(5):

74 DL Helmreich, DB Parfitt, X-Y Lu, H Akil and SJ Watson (2005). Relation between the hypothalamic-pituitary-thyroid (HPTI) axis and the hypothalamic-pituitary-adrenal (HPA) axis during repeated stress. Neuroendocrinology, 81: Wei Q, Lu X-Y, Liu L, Schafer G, Shieh KR, Burke S, Robinson TE, Watson SI, Seasholtz AF, Akil H (2004) Glucocorticoid receptor overexpression in forebrain: A mouse model of increased emotional lability. Proc Natl Acad Sci USA, 101(32): Kaelin CB, Xu AW, Lu X-Y, Barsh GS (2004). Transcriptional regulation of Agoutirelated protein (Agrp) in transgenic mice. Endocrinology, 145(12) Lu X-Y, Barsh GS, Akil H, Watson SJ (2003) Interaction between alpha-melanocytestimulating hormone and corticotropin-releasing hormone in the regulation of feeding and hypothalamo-pituitary adrenal responses. Journal of Neuroscience, 23(21): He L, Lu X-Y, Jolly AF, Eldridge AG, Watson SJ, Jackson PK, Barsh GS, Gunn TM (2003). Spongiform encephalopathy caused by defects of an E3 ubiquitin ligase in mahoganoid mice. Science, 299: Lu X-Y, Shieh KR, Kabbaj M, Barsh GS, Akil H, Watson SJ (2002) Diurnal rhythm of Agouti-related protein and its relation to corticosterone and food intake. Endocrinology, 143(10): He L, Gunn TM, Bouley DM, Lu X-Y, Watson SJ, Duke-Cohan JS, Barsh GS (2001) A biochemical function for attractin (mahogany) in agouti-induced pigmentation and obesity. Nature Genetics, 27(1): Lu X-Y (2001) Role of the central melanocortin signaling in eating disorders (review). Psychopharmacology Bulletin, 35(4): Lu X-Y, Bagnol D, Burke S, Akil H, Watson SJ (2000) Differential expression and regulation of OX1 and OX2 orexin/hypocretin receptors in the brain upon fasting. Hormones and Behavior, 37(4): Bagnol D*, Lu X-Y*, Kaelin D, Day HEW, Ollmann M, Gantz I, Akil H, Barsh GS, Watson SJ (1999) Anatomy of an endogenous antagonist: Relationship between agoutirelated protein and proopiomelanocortin in brain. Journal of Neuroscience,19:RC26, 1-7. (*equally contributed). Lu X-Y, Gunn TM, Shieh KR, Barsh GS, Akil H, Watson SJ (1999) Distribution of mahogany mrna in the rat central nervous system. FEBS Letters, 462(1-2): Ghasemzadeh MB, Nelson LC, Lu X-Y, Kalivas PW (1999) Neuroadaptations in ionotropic and Metabotropic glutamate receptor mrna produced by cocaine treatment. Journal of Neurochemistry, 72: Lu X-Y, Ghasemzadeh MB, Kalivas PW (1999) Regional distribution and cellular localization of GABAB1 messenger RNA in the rat brain. Journal of Comparative Neurology, 407(3):

75 LuX-Y, Ghasemzadeh MB, Kalivas PW (1999) Expression of NMDAR1, GluR1, GluR2 and mglur5 glutamate receptor subunit mrnas in the accumbal projection neurons. Molecular Brain Research, 63(2): Lu X-Y, Ghasemzadeh MB, Kalivas PW (1998) Expression of D1 receptor, D2 receptor, substance P and enkephalin mrnas in the neurons projecting from the nucleus accumbens. Neuroscience, 82: Lance McMahon Assistant Professor of Pharmacology Ph.D., Texas A&M University Office: (210) mcmahonl@uthscsa.edu Drug dependence can have devastating consequences not only for the dependent individual, but also for family, friends, public health, and society. Developing effective therapies for drug dependence requires an understanding of the environmental, behavioral, and pharmacologic determinants responsible for drug use. Research in my laboratory integrates principles of behavior and receptor theory to identify mechanisms in the nervous system responsible for the abuse liability of sedative-hypnotics, opioids, and cannabinoids. Cannabis use, in particular, has received considerable scrutiny. From the perspective of public health, cannabis appears to have some therapeutic value on the one hand and deleterious effects on performance and quality of life on the other. Current research emphasizes: 1) Mechanism(s) of cannabinoid action. The effects of cannabis that lead to its selfadministration are hypothesized to be mediated by a common mechanism at a particular cannabinoid receptor subtype. Results of ongoing studies suggest that a single mechanism does not account for the behavioral effects of cannabinoids. 2) Dependence that results from chronic cannabinoid treatment. Learned behavior is being used to better understand the neuropharmacology of cannabis dependence, as defined by withdrawal upon discontinuation of cannabinoid treatment, and to identify medicines that might alleviate withdrawal in those seeking to achieve abstinence in the clinic. Selected Recent Publications McMahon, L.R., Amin, M.R. & France, C.P. (2005). SR A differentially attenuates the behavioral effects of Δ 9 - tetrahydrocannabinol in rhesus monkeys. Behavioural Pharmacology. 16:

76 McMahon, L.R., & France, C.P. (2005). Combined discriminative stimulus effects of midazolam with other positive GABA A modulators and GABA A receptor agonists in rhesus monkeys. Psychopharmacology, 178: McMahon, L.R., & France, C.P. (2005). Negative GABA A modulators attenuate the discriminative stimulus effects of benzodiazepines and the neuroactive steroid pregnanolone in rhesus monkeys. Psychopharmacology, 181: McMahon, L.R., Sell, S.L., & France, C.P. (2004). Cocaine and other indirect-acting monoamine agonists differentially attenuate a naltrexone discriminative stimulus in morphine-treated rhesus monkeys. Journal of Pharmacology and Experimental Therapeutics, 308: McMahon, L.R., Coop, A., France, C.P., Winger, G., & Woolverton, W.L. (2003). Evaluation of the reinforcing and discriminative stimulus effects of 1,4-butanediol and gamma-butyrolactone in rhesus monkeys. European Journal of Pharmacology, 466: McMahon, L.R., & France, C.P. (2003). Discriminative stimulus effects of the cannabinoid antagonist, SR A, in Δ 9 - tetrahydrocannabinol-treated rhesus monkeys. Experimental and Clinical Psychopharmacology, 11: McMahon, L.R., Filip, M., & Cunningham, K.A. (2001). Differential regulation of the mesoaccumbens circuit by serotonin 5-hydroxytryptamine (5-HT) 2A and 5-HT 2C receptors. Jorunal of Neuroscience, 21: Steven W. Mifflin Professor of Pharmacology Ph.D., The University of Texas Medical Branch, Galveston Office: (210) mifflin@uthscsa.edu The brain plays a critical role in maintaining normal blood pressure. During the past few years it has become clear that neurons in the brain that regulate blood pressure exhibit a surprising degree of plasticity in response to chronic changes in physiological state. The physiology and pharmacology of synaptic integration within the central nervous system are altered in hypertension and chronic hypoxic states. The goal of my laboratory is to characterize the plasticity of central neurons that regulate blood pressure in pathological states. We are using a multi-disciplinary approach based upon in vivo (intracellular and extracellular) and in vitro (whole cell patch clamp) electrophysiological techniques. Immunohistochemical techniques are used to determine the relationships between functionally identified neurons and putative transmitters or modulators. Molecular biological techniques are used to phenotype neurons and examine alterations in the expression of ligand-gated and voltage dependent ion channels in hypertensive and hypoxic rats. These studies will advance 76

77 our understanding of blood pressure regulation under normal conditons and provide insights into the etiology of pathophysiological states where the brain does not regulate blood pressure normally (e.g. hypertension, heart failure). Selected Publications Zhang, W. and S.W. Mifflin. Chronic hypertension enhances post-synaptic effect of baclofen in the NTS. Hypertension, 49:1-5, Zhang, W. and S.W. Mifflin. Modulation of synaptic transmission to second-order peripheral chemoreceptor neurons in caudal NTS by alpha1-adrenoreceptors. J of Pharm. and Exptl. Therapeutics, 320: , Cunningham, J.T., M. Herrera-Rosales, M.A. Martinez and S.W. Mifflin. Identification of active central nervous system sites in renal wrap hypertensive rats. Hypertension, 49: , de Paula, P.M., Tolstykh, G. and S.W. Mifflin. Chronic intermittent hypoxia alters NMDA and AMPA-evoked currents in NTS neurons receiving carotid body chemoreceptor inputs. Am. J. Physiol. (Reg. Int. Comp.), 292: , Tolstykh, G., P.M. de Paula and S.W. Mifflin. Voltage-dependent calcium currents are enhanced in NTS neurons isolated from renal wrap hypertensive rats. Hypertension, 49: , Mifflin, S.W. New insights into the electrophysiology of brainstem circuits controlling blood pressure. Current Hypertension Reports, 9: , David Morilak Professor of Pharmacology Ph.D., Princeton University Office: (210) morilak@uthscsa.edu The focus of research in our laboratory is on the brain neurotransmitter norepinephrine (NE) and its role in a) acute behavioral, cognitive and endocrine responses to stress; b) adaptive and maladaptive responses to chronic stress; and c) regulatory mechanisms of action of psychotherapeutic drugs. NE is an important neuromodulatory transmitter which plays a critical role in the acute response to stress by influencing arousal and sensorimotor response characteristics, and by integrating autonomic and endocrine responses with behavior. Using in vivo microdialysis and behavioral pharmacology, we investigate the role of NE in modulating anxiety-like behavioral and neuroendocrine responses to acute stress, and in enhancing higher-order cognitive processes in the medial prefrontal cortex related to arousal and attention. At a molecular and cellular level, we study regulatory changes in gene expression induced in brain noradrenergic neurons in response to stress, including expression of mrna for synthetic enzymes, the 77

78 NE transporter and post-synaptic adrenergic receptors, using in situ hybridization. A second project addresses changes produced by chronic stress in the brain noradrenergic system that may contribute to the development of stress-related pathology such as depression, PTSD or anxiety disorders. Another major effort is to understand the regulatory changes in NE function that contribute to the beneficial therapeutic effects of antidepressant and anxiolytic drugs. Experimental approaches include local drug microinjections into stress-related brain regions; in vivo microdialysis to measure neurotransmitter release in behaving rats; in situ hybridization, immunohistochemistry and receptor autoradiography; radioimmunoassay for plasma hormone measures; behavioral measures of cognition, arousal, anxiety and defensive responses; and the application and analysis of chronic metabolic and psychogenic stressors. These studies will help us to understand the differential roles of NE and other monoaminergic neurotransmitters in a number of complex physiological contexts, including the response to acute stress and the development of chronic stress-related psychopathology such as anxiety or depression, and also in the mechanisms of beneficial action of psychotherapeutic agents such as antidepressants. Selected Publications Lapiz, M.D.S., Bondi, C.O. and Morilak, D.A. (2007) Chronic treatment with desipramine improves cognitive performance of rats in an attentional set shifting test. Neuropsychopharmacology, 32: Bondi, C.O., Barrera, G., Lapiz, M.D.S., Bedard, T., Mahan, A. and Morilak, D.A. (2007) Noradrenergic facilitation of shock-probe defensive burying in lateral septum of rats, and modulation by chronic treatment with desipramine. Prog. Neuropsychopharmacol. Biol. Psychiatry, 31: Barrera, G., Poulin, J.F., Hernandez, A., Laforest, S., Drolet, G., Morilak, D.A. (2006) Galanin-mediated anxiolytic effect in rat central amygdala is not a result of co-release from noradrenergic terminals. Synapse, 59: Lapiz, M.D. and Morilak, D.A. (2006) Noradrenergic modulation of cognitive function in rat medial prefrontal cortex as measured by attentional set shifting capability. Neurosci., 137: Morilak, D.A., Barrera, G., Echevarria, D.J., Garcia, A.S., Hernandez, A., Ma, S., Petre, C.O. (2005) Role of brain norepinephrine in the behavioral response to stress. Prog. Neuropsychopharmacol. Biol. Psychiatr., 29: Frazer, A. and Morilak, D.A. (2005) What should animal models of depression model? Neurosci. Biobeh. Revs., 29: Echevarria, D.J., Hernandez, A., Diogenes, A., Morilak, D.A. (2005) Administration of the galanin antagonist M40 into lateral septum attenuates shock probe defensive burying behavior in rats. Neuropeptides, 39:

79 Ma, S. and Morilak, D.A. (2005) Chronic intermittent cold stress sensitizes the HPA response to a novel acute stress by enhancing noradrenergic influence in the rat paraventricular nucleus. J. Neuroendocrinol., 17: Ma, S. and Morilak, D.A. (2005) Norepinephrine release in medical amygdala facilitates activation of the HPA axis in response to acute immobilization stress. J. Neuroendocrinol., 17: Garcia, A.S., Barrera, G., Burke, T.F., Hensler, J.G. and Morilak, D.A. (2004) Autoreceptor-mediated inhibition of norepinephrine release in rat medial prefrontal cortex is maintained after chronic desipramine treatment. J. Neurochem., 91: Ma, S. and Morilak, D.A. (2004) Induction of Fos expression by acute immobilization stress is reduced in locus coeruleus and medial amygdala of Wistar-Kyoto rats compared to Sprague-Dawley rats. Neurosci., 124: Morilak, D.A. and Frazer, A. (2004) Antidepressants and Brain Monoaminergic Systems: A Dimensional Approach to Understanding Their Efficacy in Depression and Anxiety Disorders. Int. J. Neuropsychopharmacol., 7: Benmansour, S., Altamirano, A.V., Jones, D.J., Sanchez, T.A., Gould, G.G., Pardon, M.-C., Morilak, D.A., Frazer, A. (2004). Regulation of the norepinephrine transporter by chronic administration of antidepressants. Biol. Psychiat., 55: Pardon, M.-C., Ma, S. and Morilak, D.A. (2003). Chronic cold stress sensitizes brain noradrenergic reactivity and noradrenergic facilitation of the HPA stress response in Wistar Kyoto rats, Brain Res., 971: Khoshbouei, H., Cecchi, M., Dove, S., Javors, M. and Morilak, D.A. (2002) Behavioral reactivity to stress: Amplification of stress-induced noradrenergic activation elicits a galanin-mediated anxiolytic effect in central amygdala. Pharmacol., Biochem., and Behav., 71: Khoshbouei, H., Cecchi, M.. and Morilak, D.A. (2002) Modulatory effects of galanin in the lateral bed nucleus of the stria terminalis on behavioral and neuroendocrine responses to acute stress. Neuropsychopharmacol., 27: Cecchi, M., Khoshbouei, H., Javors, M. and Morilak, D.A. (2002) Modulatory effects of norepinephrine in the lateral bed nucleus of the stria terminalis on behavioral and neuroendocrine responses to acute stress. Neurosci., 112: Pardon, M.-C., Gould, G.G., Garcia, A., Phillips, L., Cook, M.C., Miller, S.A., Mason, P.A. and Morilak, D.A. (2002). Stress reactivity of the brain noradrenergic system in three rat strains differing in their neuroendocrine and behavioral responses to stress: Implications for susceptibility to stress-related neuropsychiatric disoders. Neurosci., 115: Cecchi, M., Khoshbouei, H., and Morilak, D.A. (2002). Modulatory effects of norepinephrine, acting on alpha1-receptors in the central nucleus of the amygdala, on 79

80 behavioral & neuroendocrine responses to acute immobilization stress. Neuropharmacol., 43: Ravi Ranjan Assistant Professor of Pharmacology The Sam & Ann Barshop Center for Longevity & Aging Studies Ph.D., Tata Institute of Fundamental Research - Bombay, India Office: (210) ranjan@uthscsa.edu The genetics of aging in Drosophila and the mechanism of neurotransmitter secretion at the synapse Overview: The roots of cognition, behavior, learning and memory are embedded in the brain s intricate network of neuronal cells and their specialized points of contact, the synapses. Alterations in synaptic signaling underlie a variety of forms of synaptic plasticity associated with learning, memory, and aging and have important roles in the pathogenesis of age-related neurodegenerative disorders, including Alzheimer s disease, Parkinson s disease, Huntington s disease, epilepsy and stroke. My research interests can be divided into two parts a.) What are the molecular mechanisms underlying coordinated behavior, cognition, learning and memory? b.) How are these mechanisms affected by inherited neurological diseases and age-related neurological decline? The focus of my research is to comprehensively elucidate the molecular mechanisms underlying synaptic function, plasticity, and aging. We are combining molecular biology, electrophysiology, imaging and behavioral approaches with Drosophila genetics to investigate the molecular mechanisms involved in neuronal signaling and the underlying changes that cause neurological diseases and neuronal aging. There are two primary areas of research within my laboratory: A.) Genetic dissection of synaptic plasticity and aging: We are focusing on a provocative G-protein coupled receptor (GPCR), Methuselah, previously shown to increase lifespan. B.) Genetic dissection of Ca 2+ -regulated neurotransmitter release: We are studying the family of proteins containing C2 domains, particularly synaptotagmin, and their roles in membrane traffic. A.) G-Protein dependent synaptic modulation: In biological systems, physiological responses to extracellular signals are elicited by activation of specific receptor proteins such as G-protein coupled receptors (GPCRs). Important modulatory roles for GPCRs have been suggested for aging, sleep, synaptic release and other cellular responses. Adaptive modifications of synaptic efficacy are very important for normal brain functioning and this is accomplished by signaling cascades. G-protein coupled receptors are important members of these processes. 80

81 Methuselah: Methuselah mutants were isolated in a screen for mutations affecting resistance to stress and aging. Methuselah loss-of-function mutations increase lifespan by 35% and also increase stress resistance. Our analysis of synaptic transmission at the fly larval neuromuscular junction revealed that methuselah mutants have reduced transmitter release and indicate that Methuselah is a modulator of release, perhaps altering a step downstream from Ca 2+ entry. We find an interesting paradox in this phenotype: all known synaptic mutants with a reduction in vesicle release die prematurely, unlike Methuselah, which lives longer. So far the relationship between aging and reduced release has not been addressed. This is an open and interesting problem currently being investigated in my laboratory. Recently the ligands for Methuselah have been identified which encode for an ε- subunit of ATP syntheses. Mutations in the ligands also extend lifespan and preliminary analysis suggests that they may modulate presynaptic release like methuselah. This early analysis provides convincing evidence that Methuselah, a G-protein coupled receptor and other components of its pathway may be very important for synaptic plasticity and subsequently for processes of neuronal aging. We are using Drosophila as a neuronal aging model to understand the underlying mechanisms. Ongoing research Our current analysis revolves around four major questions concerning the role of Methuselah in synaptic release in relation to cellular plasticity. (1) Are the reduction in neurotransmitter release and aging causally related? (2) How do Methuselah and its ligands control synaptic release and aging? (3) How do these components interact with synaptic release machinery to modulate aging? (4) What are the downstream components of the Methuselah pathway regulating vesicle docking/priming? The systematic analysis of the Methuselah receptor, its ligands and newly found components of this pathway will enable us to understand how this pathway modulates the synapse. We are analyzing the known components and at the same time looking for new molecules by genetic interaction and screens. B.) Ca 2+ -triggered vesicle fusion: Since the discovery that Ca 2+ is essential for fast, regulated neurotransmitter release, neurobiologists have been in search of the relevant molecules that sense the Ca 2+ flux. In the past decade synaptic proteins such as SNAREs and Synaptotagmin I were shown to be central to the calcium triggered fusion. Yet despite considerable effort, the definitive roles of Synaptotagmin I and other key synaptic proteins have not been determined. The problem is made more complex by the fact that Synaptotagmins are members of a large family, most of which bind to Ca 2+. Initial analysis suggests that family members may function in a combinatorial fashion to sense Ca 2+ at a given synapse. We are exploring the role of individual synaptotagmin isoforms and the interrelationship between different isoforms to understand their synaptic functions. Beside synaptotagmins, we are in the process of analyzing novel synaptic genes and have begun genetic screens to identify additional components that function in synaptic transmission by directly screening for electrophysiological defects. Summary: To comprehensively address the issue of synaptic vesicle exocytosis and its modulation, we have chosen Drosophila as a model system which can be easily 81

82 manipulated at multiple levels. I plan to combine genetics with molecular biology, electrophysiology, imaging and behavior. Systematic genetic dissection of these different genes will help in understanding their individual and combinatorial roles in synaptic plasticity and aging. Selected Publications Interactions between members of the Drosophila exocyst complex and characterization of a sec6 mutant. M. Murthy, Ravi Ranjan, N. Denef, T. Schupbach and Thomas L. Schwarz. J Cell Sci Mar 15; 118(Pt 6): Epub 2005 Feb. Presynaptic Regulation of Neurotransmission in Drosophila by the G Protein-Coupled Receptor Methuselah Wei Song*, Ravi Ranjan*, Peter Bronk, Ken Dawson-Scully, Leo Marin, Laurent Seroude, YiJyun Lin, Zhiping Nie, Harold L. Atwood, Seymour Benzer and Konrad E. Zinsmaier. Neuron, 2002, Vol. 36(1) (*Equal contribution). Synaptotagmins I and IV promote transmitter release independently of Ca2+ binding in the C2A Domain Iain M. Robinson*, Ravi Ranjan* and Thomas L. Schwarz Nature, 2002, Vol. 418(6895): (*Equal contribution). Drosophila Liprin- and the Receptor Phosphatase Dlar Control Synapse Morphogenesis Nancy Kaufmann, Jamin DeProto, Ravi Ranjan, Hong Wan, and David Van Vactor. Neuron, 2002, Vol. 34: Overexpression of Cysteine-String Proteins in Drosophila Reveals Interactions with Syntaxin Zhiping Nie*, Ravi Ranjan*, Julia Wenniger, Susie N. Hong, Peter Bronk, and Konrad E. Zinsmaier. The Journal of Neuroscience, 1999, Vol. 19: (*Equal contribution). Cysteine String Protein Is Required for Calcium Secretion Coupling of Evoked Neurotransmission in Drosophila But Not for Vesicle Recycling Ravi Ranjan, P. Bronk, and K. E. Zinsmaier. The Journal of Neuroscience, 1998, Vol. 18(3): James Roberts Professor of Pharmacology Ph.D., University of Oregon, Eugene Office: (210) robertsjl0@uthscsa.edu The major research area in the Roberts lab focuses on the role of growth factors, cytokines and estrogens in mediating protection/recovery of the brain from damage due to oxidative stress, focusing on the nigro-striatal pathway and its degeneration in Parkinson s disease. This whole system is characterized from a perspective of the changes that occur as the animal s age progresses. Astrocytes, the largest cell population in the brain regulate neuronal homeostasis and have been implicated in affecting the viability and functioning of surrounding neurons under stressed conditions. In addition, much attention has been focused on estrogen interactions in non-neuronal cell types. Recent data from our lab 82

83 suggests indirect actions of estrogen through ERα and neighboring glia to protect dopamine neurons against MPP + toxicity in mouse mesencephalic cultures. These results prompted us to study estrogen signaling in astrocytes to evaluate the mechanism of estrogens indirect neuroprotective effects on DA neurons. Pure astrocyte cultures were analyzed for membrane ERα expression and signal transduction responses to 17β-estradiol (E 2 ) treatment. ERα was found to co-localize with the lipid raft marker, flotillan-1. E 2 time course revealed a significant increase in Akt phosphorylation at 5-60 minutes. E 2 also induced phosphorylation of the downstream transcription factor, CREB. These results were then analyzed in primary mesencephalic cultures in the presence of MPP +, which selectively damages DA neurons. Cultures treated with 17β-estradiol and the membrane impermeable estrogen, E 2 -BSA were both neuroprotective against MPP + toxicity suggesting membraneinitiated neuroprotection. Inhibition of Akt blocked E 2 induced neuroprotection, implicating the involvement of the PI3 kinase pathway. Finally, E 2 conditioned media collected from pure astrocyte cultures rescued glial deficient mesencephalic cultures from MPP +. This study demonstrates that estrogen signaling through astrocytes and the release of soluble factor(s) contributes significantly to the neuroprotection of DA neurons. Proteomic analysis suggests that a GDNF family member, neurturin, is released into the media to elicit the protection. These studies are currently being expanded to the negative effects of androgens in this neuroprotective paradigm possibly explaining the bias of this disorder to males. In another set of studies, we have cultured astroglia from young, middle-age and old mice and observed that the older astrocytes are less capable of protecting dopaminergic neurons from oxidative stress. We are currently performing proteomic analysis on the secreted factors to determine the molecular basis for these differences. Finally, the positive and negative role of immune cell invasion into the damaged nigro-striatal area is also being investigated in in vivo mouse models of PD. Selected Publications Bains M, Cousing JA, Roberts JL. Neuroprotection by estrogen against MPP+-induced dopamine neuron death is mediated by ERalpha in primary cultures of mouse mesencephalon, Experimental Neurology, 204: (2007) Price D, Daws LC, Owens WA, Gould GG, Frazer A, Roberts JL and Giuffrida. CB1- independent inhibition of dopamine transporter activity by cannabinoids in mouse dorsal striatum. J Neurochem. 101: (2007) Jeske NA, Berg KA, Cousins JC, Ferro ES, Clarke WP, Glucksman MJ, Roberts JL. Modulation of bradykinin signaling by EP24.15 and EP24.16 in cultured trigeminal ganglia. J Neurochem. 97:13-21 (2006) Wu TJ, Mani SK, Glucksman MJ, Roberts JL. Stimulation of luteinizing hormonereleasing hormone (LHRH) gene expression in GT1-7 cells by its metabolite, LHRH-(1-5). Endocrinology. 146(1):280-6 (2005) 83

84 Jeske N, Glucksman MJ and Roberts JL. Metalloendopeptidase EC is Constitutively Released from the Exofacial Leaflet of Lipid Rafts in Neuronal GT1-7 Cells. J Neurochemistry, 90(4):819-28, (2004). Russell Sanchez Assistant Professor of Pharmacology Ph.D., New York University Office: (210) Lab: (210) sanchezr0@uthscsa.edu The electrical activity of neurons and other excitable cells is generated by the combined action of chemically and electrically gated transmembrane ion channels. Most psychoactive drugs exert their effect by directly or indirectly modifying neuronal ion channel function in the brain. My research is aimed broadly at understanding the mechanisms by which ion channels are dynamically regulated and at elucidating the roles of pathological channel activity in neurological disease. The overall goal is to identify pathological states of ion channel function that may be targeted by pharmacological agents without interfering with physiological channel function. My research specifically has focused on understanding the modulation of ion channels gated by the neurotransmitters glutamate and gamma-aminobutyric acid (GABA) and their roles in the generation of acute seizures and chronic epilepsy in the developing brain. Glutamate receptors mediate most fast excitatory synaptic transmission in the brain, whereas GABA receptors mediate most inhibitory transmission. Alterations in the function of either of these neurotransmitter systems can render the brain abnormally susceptible to seizures. Using a combination of electrophysiological and molecular approaches, we are investigating how glutamate and GABA receptors are regulated during early development in the rat hippocampus. The immature brain is especially susceptible to seizures, and we have observed maturational differences in the molecular composition and function of glutamate receptors that are likely to contribute to this increased seizure susceptibility. Additionally, early life seizures increase the risk of chronic epilepsy, and we further have observed pathological changes in glutamate and GABA receptor function following generalized seizures in the neonatal rat. Additional work is aimed at establishing a causal link between altered channel function and neuronal hyperexcitability using tissue culture preparations in which channel expression and function can be directly manipulated in the absence of previous seizures. A thorough understanding of the maturational and activity-dependent regulation of ion channels is necessary to develop optimal age-specific therapies to treat neonatal seizures and to prevent long-term epileptogenesis. 84

85 Selected Publications Sarnat, Harvey B.; Simeone, Timothy A.; Sanchez, Russell M., and Rho, Jong M. Molecular biology and ontogeny of glutamate receptors in the mammalian central nervous system. Journal of Child Neurology, 19(5): , Cavazos, JE and Sanchez, R. Pathophysiology of seizures and epilepsy. In Rho, JM, Sankar, R, and Cavazos, JE, (eds.), Epilepsy: Scientific Foundations of Clinical Practice. Marcel Dekker, Sanchez, RM and Jensen, FE. Maturational regulation of glutamate receptors and their role in neuroplasticity. In Herman, B, (ed.), Glutamate and Addiction, pp Humana Press, Jensen, FE and Sanchez, RM. Why does the developing brain demonstrate heightened susceptibility to febrile and other provoked seizures? In: Baram, TZ and Shinnar, S (eds.), Febrile Seizures, pp Academic Press (2002). Sanchez, RM, Koh, S, Rio, C, Wang, C, Lamperti, ED, Sharma, D, Corfas, G, and Jensen, FE. Decreased GluR2 expression and enhanced epileptogenesis in immature rat hippocampus following perinatal hypoxia-induced seizures. Journal of Neuroscience 2001; 21(20): Sanchez, RM and Jensen, FE. Maturational aspects of epilepsy mechanisms and consequences for the immature brain. Epilepsia 42(5): , Sanchez, RM, Wang, C, Gardner, G, Orlando, L, Tauck, DL, Rosenberg, PA, Aizenman, E, and Jensen, FE. Novel role for the NMDA receptor redox modulatory site in the pathophysiology of seizures. J. Neurosci. 20(6): , Sanchez, R, Surkis, A, and Leonard, CS. Voltage-clamp analysis and computer simulation of a novel cesium-resistant A-current in guinea pig laterodorsal tegmental neurons. J. Neurophysiol. 79: , Alexander M.M. Shepherd Professor of Pharmacology and Medicine M.D., Ph.D., St. Andrews University, Scotland Office: (210) ashepherd@uthscsa.edu The Division of Clinical Pharmacology is based in the Departments of Pharmacology and Medicine and occupies offices and patient and analytical areas in the McDermott 85

86 Building. The clinical commitment includes the Hypertension Service of the University Medical System. Clinical studies are based on this patient population. Selected Publications Stagni G, O'Donnell D, Liu YJ, Kellogg DL, Morgan T, Shepherd AM. Intradermal microdialysis: kinetics of iontophoretically delivered propranolol in forearm dermis. J Control Release. Feb 3;63(3):331-9, Jamieson MJ, Gonzales GM, Jackson TI, Koerth SM, Romano WF, Tan DX, Shepherd AMM. Evaluation of the IITC tail cuff blood pressure recorder in the rat against traarterial pressure according to criteria for human devices. Am J Hypertens 10(2):209-16, Oparil S, Kobrin I, Abernethy DR, Levine BS, Reif MC, Shepherd AMM. Dose-response characteristics of mibefradil, a novel calcium antagonist, in the treatment of essential hypertension. Am J Hypertens 10(7 Pt 1):735-42, Stagni G, Shepherd AMM, Liu Y, Gillespie WR. Generalized models of drug response kinetics: characterization and predition of verapamil pharmacodynamics with respect to plasma concentration or input-rate Stagni G, Shepherd AMM, Liu Y, Gillespie WR: Bioavailability assessment from pharmacologic data: methods and clinical evaluation. J Pharm Biopharmaceutics 25(3):157, Liu, YJ, Stagni G, Judith G. Walden, B.S. Shepherd AMM, Lichtenstein MJ. Thioridazine Dose-related Effects on Biomechanical Force Platform Measures of Sway in Young and Elderly Men. Journal of the American Geriatrics Society Thomas Slaga Professor of Pharmacology Ph.D., University of Arkansas Medical Center - Little Rock Office: (210) slagat@uthscsa.edu The research in Dr. Thomas Slaga's laboratory is focused on glucocorticoid hormones (GC), very potent inhibitors of physiological DNA synthesis in keratinocytes in vivo. These hormones are also very effective in preventing carcinogen- and tumor promoterinduced skin hyperplasia, inflammation, and mouse skin tumor formation when applied to skin together with a carcinogen or a tumor promoter. We and others have shown, however, that the GC do not affect the growth of either established papillomas, squamous cell carcinomas (SCC), or transformed keratinocytes in vitro. In addition, we recently found that the GC do not affect glucocorticoid-responsive genes in transformed keratinocytes both in vitro and in vivo. We have generated skin-targeted transgenic mice over-expressing the GR under the control of the keratin 5 (K5) promoter. These adult transgenic mice have impaired proliferative and inflammatory responses to skin 86

87 tumor promoters. Our initial studies showed that the K5.GR transgenic animals are resistant to ras-induced tumorigenesis. The constitutively nuclear overexpression and activation of the GR in the epidermis dramatically inhibited skin tumor development in K5.GR/ras+ double transgenic mice in terms of number of animals that develop tumors, number of tumors per animal, and tumor size. In another study we plan to determine the mechanism(s) of synergistic action of the natural source compounds, known to inhibit one or more stages of skin carcinogenesis, i.e., initiation and promotion/progression. The concurrent topical and systemic (i.e., dietary) treatment with selected natural source inhibitors of different stages of skin carcinogenesis result in synergistic effects leading to more efficient prevention of skin cancer. The natural source inhibitors to be tested include ellagic acid, imperatorin from the family of coumarins, proanthocyanidin B-2-gallate, (-)-epigallocatechin from the family of green tea polyphenols, N- acetylcysteine, calcium D-glucarate, lycopene, carnosol and ursolic acid from rosemary extract, and resveratrol. We propose to initially utilize a number of very predictive shortterm in vitro and in vivo tests in order to identify the mechanism(s) and to differentiate the potencies of selected inhibitors at various concentrations under standard conditions. The most effective compounds will then be studied in long-term tumor experiments utilizing a 7,12-dimethylbenz[a]anthracene (DMBA)-induced 12-O-tetradecanoylphorbol- 13-acetate (TPA)-promoted multistage carcinogenesis model in SENCAR mice. Selected Publications Garcia GE, Wisniewski HG, Lucia MS, Arevalo N, Slaga TJ, Kraft SL, Strange R, Kumar AP. 2-Methoxyestradiol inhibits prostate tumor development in transgenic adenocarcinoma of mouse prostate: role of tumor necrosis factor-alpha-stimulated gene 6. Clin Cancer Res., 12: , Curtin GM, Hanausek M, Walaszek Z, Zoltaszek R, Swauger JE, Mosberg AT, Slaga TJ. Short-term biomarkers of cigarette smoke condensate tumor promoting potential in mouse skin. Toxicol Sci., 89:66-74, Ghosh R, Nadiminty N, Fitzpatrick JE, Alworth WL, Slaga TJ, Kumar AP. Eugenol causes melanoma growth suppression through inhibition of E2F1 transcriptional activity. J Biol Chem., 280(7): , Curtin GM, Hanausek M, Walaszek Z, Mosberg AT, Slaga TJ. Short-term in vitro and in vivo analyses for assessing the tumor-promoting potentials of cigarette smoke condensates. Toxicol Sci., 81:14-25, Hanausek M, Walaszek Z, Viaje A, LaBate M, Spears E, Farrell D, Henrich R, Tveit A, Walborg EF Jr, Slaga TJ. Exposure of mouse skin to organic peroxides: subchronic effects related to carcinogenic potential. Carcinogenesis., 25: , Walaszek Z, Hanausek M, Narog M, Raich PC, Slaga TJ. Mechanisms of lung cancer chemoprevention by D-glucarate. Chest, 125(5 Suppl):149S-50S, Walaszek Z, Hanausek M, Slaga TJ. Mechanisms of chemoprevention. Chest, 125(5 Suppl):128S-33S,

88 Budunova IV, Kowalczyk D, Perez P, Yao YJ, Jorcano JL, Slaga TJ. Glucocorticoid receptor functions as a potent suppressor of mouse skin carcinogenesis. Oncogene, 22: , Ghosh R, Ott AM, Seetharam D, Slaga TJ Kumar AP. Cell cycle block and apoptosis induction in a human melanoma cell line following treatment with 2-methoxyoestradiol: therapeutic implications? Melanoma Res., 13: , Kumar AP, Garcia GE, Orsborn J, Levin VA, Slaga TJ. 2-Methoxyestradiol interferes with NF kappa B transcriptional activity in primitive neuroectodermal brain tumors: implications for management. Carcinogenesis, 24: , Hanausek M, Walaszek Z, Slaga TJ. Detoxifying cancer causing agents to prevent cancer. Integr Cancer Ther., 2: , Gasparian AV, Yao YJ, Lu J, Yemelyanov AY, Lyakh LA, Slaga TJ Budunova IV. Selenium compounds inhibit I kappa B kinase (IKK) and nuclear factor-kappa B (NFkappa B) in prostate cancer cells. Mol Cancer Ther., 1: , Perez P, Page A, Bravo A, Del Rio M, Gimenez-Conti I, Budunova I, Slaga TJ Jorcano JL. Altered skin development and impaired proliferative and inflammatory responses in transgenic mice overexpressing the glucocorticoid receptor. FASEB J., 15(11): , Kumar AP, Garcia GE, Slaga TJ. 2-methoxyestradiol blocks cell-cycle progression at G(2)/M phase and inhibits growth of human prostate cancer cells. Mol Carcinog., 2001 Jul;31(3): Spiegelman VS, Stavropoulos P, Latres E, Pagano M, Ronai Z, Slaga TJ, Fuchs SY. Induction of beta-transducin repeat-containing protein by JNK signaling and its role in the activation of NF-kappaB. J Biol Chem., 20;276: , Randy Strong Associate Professor of Pharmacology Ph.D., UT Graduate School of Biomedical Sciences, Houston, TX Office: (210) / strong@uthscsa.edu My research has two major objectives: the first is directed toward understanding receptor mechanisms involved in regulating tyrosine hydroxylase (TH) gene expression, the rate limiting enzyme in the synthesis of catecholamines. The latter substances are crucially involved in various life-sustaining functions and are implicated in diseases such as hypertension, depression and Parkinson s disease. We are examining the signal transduction mechanisms that mediate the effects of selected neurotransmitter and neuromodulators on TH gene expression in a cultured adrenal chromaffin cell line. Most recently, we have focused on vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide (PACAP) receptors 88

89 and glucocorticoid receptors. We have investigated both transcriptional and posttranscriptional responses to PACAP and VIP and found that the PAC1 receptor distinguishes between the two agonists by stabilizing TH mrna in response to PACAP, but not VIP. We are investigating intracellular signaling pathways in this response. We also recently identified the glucocorticoid responsive element in the promoter region of the TH gene. We are examining how second messenger pathways that are stimulated by neuropeptide receptors modulate the transcriptional responses to glucocorticoids. The second research objective is directed toward understanding the role of oxidative stress in the aging brain. One project is aimed at determining how reactive catecholamine metabolites contribute to neuropathology of aging and Parkinson s disease. We are particularly interested in the role that 3,4- dihydroxyphenylacetaldehyde (DOPAL) plays in degeneration of dopamine neurons. This highly reactive metabolite of dopamine becomes elevated in Parkinson s disease and is neurotoxic. Rotenone, a pesticide that reproduces the pathology of Parkinson s disease in rats, has been shown to elevate DOPAL in cultured cells. DOPAL is believed to be cleared by the mitochondrial aldehyde dehydrogenase (ALDH2). We have developed an ALDH2 knockout mouse to determine the role of this enzyme in DOPAL catabolism. We are also using this new mouse model to study the role of DOPAL in the pathology of Parkinson s disease. Selected Publications Strong, R., Reddy V., Morley, J. Cholinergic deficits in the septal-hippocampal pathway of the SAM-P8 senescence accelerated mouse. Brain Res. 966, , Corbit, J. Hagerty,T., Fernandez,E., Morgan, W.W. and Strong, R. Transcriptional and posttranscriptional regulation of tyrosine hydroxylase messenger RNA in PC12 cells during persistent stimulation by VIP and PACAP38: Differential regulation by protein kinase A- and protein kinase C-dependent pathways. Neuropep. 36, 34-45, Hagerty T., Fernandez E., Lynch K., Wang S. S., Morgan W. W., and Strong R. Interaction of a glucocorticoid-responsive element with regulatory sequences in the promoter region of the mouse tyrosine hydroxylase gene. J Neurochem 78, , Foster D., Strong R., and Morgan W. W. A tetracycline-repressible transactivator approach suggests a shorter half-life for tyrosine hydroxylase mrna. Brain Res Brain Res Protoc 7, , Hagerty, T, Morgan, W.W., Elango, N. and Strong, R. Identification of a glucocorticoid responsive element in the promoter region of the mouse tyrosine hydroxylase gene. J. Neurochem.,76, ,

90 Strong, R. Neurochemical changes in the aging human brain: Implications for behavioral impairment and Parkinson's disease. Geriatrics, 56 (1998). LuZhe Sun Professor of Cellular & Structural Biology and Pharmacology Ph.D., Rutgers University and UMDNJ-Robert Wood Johnson Medical School Office: (210) Our laboratory studies molecular mechanisms that regulate carcinogenesis and cancer cell growth, invasion, and metastasis using molecular and cellular biology techniques and animal model systems. One of the molecules we are currently studying is called transforming growth factor beta (TGF beta). This growth factor has been shown to inhibit tumorigenesis and growth of some early-stage adenocarcinoma cells, yet promote growth and metastasis in late-stage carcinoma cells. We are trying to understand why a given polypeptide growth factor has such opposing effects and to devise the means that can enhance its tumor-suppressing activity while antagonizing its tumor-promoting activity. We are particularly interested in determining whether TGF beta antagonists can suppress TGF beta-promoted tumor progression. Other projects in the laboratory include the role of estrogen and androgen signaling in promoting tumorigenesis and progression in the mammary gland and prostate gland, respectively. Our approaches to study regulation of gene expression include transcriptional and posttranscriptional analyses with techniques such as gene microarray, promoter activity measurements, chromosome immunoprecipitation, polymerase chain reaction, quantitative real-time RT-PCR, receptor cross-linking, immunoprecipitation and Western blotting analyses. To study gene functions, we use sense transfection, RNA interference, and retroviral transduction techniques to regulate gene expression and study the effects of altered gene expression on malignant phenotypes of cancer cells in tissue culture and in mice. Selected Publications Bandyopadhyay, A., Long Wang, Shiau Hui Chin and Lu-Zhe Sun. Inhibition of skeletal metastasis by ectopic ERα expression in ERα negative human breast cancer cell lines. Neoplasia 9: , Lei, X-F., J. Yang, R. Nichols, L-Z. Sun. Abrogation of autocrine TGF signaling induces apoptosis through the modulation of MAP kinase pathways in breast cancer cells. Exp. Cell Res. 313: , Verona, Erik V., Abdel Elkahloun, Junhua Yang, Abhik Bandyopadhyay, I-Tien Yeh, and Lu-Zhe Sun. TGFβ Signaling in prostate stromal cells supports prostate carcinoma growth by upregulating stromal genes related to tissue remodeling. Cancer Res. 67: ,

91 Bandyopadhyay, A., Joseph K. Agyin, Long Wang, Yuping Tang, Xiufen Lei, Beryl M. Story, John E. Cornell, Bradley H. Pollock, Gregory R. Mundy, and L.-Z. Sun. Inhibition of pulmonary and skeletal metastasis by a TGFβ Type I receptor kinase inhibitor. Cancer Res. 66: , Maharaj K. Ticku Professor of Pharmacology and Psychiatry Ph.D., State University of New York at Buffalo Office: (210) ticku@uthscsa.edu Dr. Ticku's major research goals are to understand and define the molecular mechanisms by which drugs modulate inhibitory and excitatory neurotransmitter systems in the mammalian central nervous system. GABA A and NMDA receptors belong to a ligand-gated super gene family. A major focus of our research is to determine the effect of chronic administration of benzodiazepines, barbiturates, neurosteroids or alcohol on regulation of GABA A receptor binding, function, gene and polypeptide expression. Chronic drug treatment could affect neurotransmission by down- or upregulation of receptors, altered coupling between various sites associated with oligomeric receptor complex and/or altered receptor efficacy. How alcohol regulates NMDA gene expression is a major focus. More recent research is aimed at establishing how chronic alcohol alters gene expression of NMDA receptors at the level of epigenetics, transcriptional factors, subsynaptic distribution and trafficking regulating proteins. These experiments are being conducted in mammalian cortical neurons under precisely controlled conditions and independent of pharmacokinetic variability. A second focus is the investigation of the effects of alcohol on NMDA receptor function and gene expression. NMDA receptors are involved in a variety of physiological processes, including maintenance of excitability, neuronal development, learning and memory as well as in the pharmacological effects of alcohol. A number of different experimental approaches are employed in these studies including receptor binding, 36Cl-flux, changes in intracellular Ca+2 levels, mrna and polypeptide level measurements. Current research involves regulation of promoter activity of NMDA R2B gene by enhancers and silencing factors (Mol Pharm papers, 2005). More recent studies include developing new probes (agonists, antagonists) to study how the date rape drug (GHB) works in the brain. These drugs have potential to be used for GHB intoxication. 91

92 Selected Publications Qiang, M., Denny, A.D., and Ticku, M.K. Chronic intermittent ethanol treatment selectively alters NMDA receptor subunits surface expression in cultured cortical neurons. Mol Pharmacol. 2007, April 17 (Epub ahead of print). Ravindran, M., Mehta, C.R., and Ticku, M.K. Effect of chronic administration of ethanol on the regulation of tyrosine kinase phosphorylation of the GABA(A) receptor subunits in the rat brain. Neurochem Res. Jul;32(7): (2007). Wang, J., Gutala, R., Sun, D., Ma, J.Z., Sheela, R.C., Ticku, M.K., Li, M.D. Regulation of platelet-derived growth factor signaling pathway by ethanol, nicotine, or both in mouse cortical neurons. Alcohol Clin Exp Res. Mar;31(3): (2007). Ravindran, C.R. and Ticku, M.K. Tyrosine kinase phosphorylation of GABA(A) receptor alpha1, beta2, and gamma2 subunits following chronic intermittent ethanol (CIE) exposure of cultured cortical neurons of mice. Neurochem Res. Sep31;(9):111-8 (2006). Sheela Rani, C.S. and Ticku, M.K. Comparison of chronic ethanol and chronic intermittent ethanol treatments on the expression of GABA(A) and NMDA receptor subunits. Alcohol. Feb;38(2):89-97 (2006). Marutha Ravindran, C.R. and Ticku, M.K. Tyrosine kinase phosphorylation of GABA(A) receptor subunits following chronic ethanol exposure of cultured cortical neurons of mice. Brain Res. May 1;1086(1):35-41 (2006). Mehta, A.K., Gould, G.G., Gupta, M., Carter, L.P., Gibson, K.M., and Ticku, M.K. Succinate semialdehyde dehydrogenase deficiency does not down-regulate gammahydroxybutyric acid binding sites in the mouse brain. Mol Genet Metab. May;88(1):86-9 (2006). Qiang, M., and Ticku, M.K. Role of Ap-1 in ethanol-induced N-methyl-D-aspartate receptor 2B subunit gene up-regulation in mouse cortical neurons. J Neurochem. Dec;95(5): (2005). Qiang, M., Rani, CS., and Ticku, MK. Neuron-restrictive silencer factor regulates the N- methyl-d-aspartate receptor 2B subunit gene in basal and ethanol-induced gene expression in fetal cortical neurons. Mol Pharmacol. 67: , Rani, CS., Qiang, M., and Ticku, MK. Role of camp response element-binding protein in ethanol-induced N-methyl-D-aspartate receptor 2B subunit gene transcription in fetal mouse cortical cells. Mol Pharmacol. 67: , Maratha, RCV and Ticku, MK. Role of CpG islands in the up-regulation of NMDA receptor NR2B gene expression following chronic ethanol treatment of cultured cortical neurons of mice. Neurochem Int. 46: ,

93 Mehta, AK and Ticku, MK. Effect of chronic ethanol administration of ethanol on GABA A receptor assemblies derived from alpha-2, alpha3-, beta2--and gamma2 subunits in the rat cerebral cortex. Brain Res. 1031: , Gutala, R., Wang, J., Kadapakkam, S., Hwang, Y., Ticku, M., and Li, MD. Microarray analysis of ethanol-induced cortical neurons reveals disruption of genes related to the ubiquitin-proteasome pathway and protein synthesis. Alcohol Clin Exp Res. 28: , Marutha, RCR and Ticku, MK. Changes in methylation pattern of NMDA receptor NR2B gene in cortical neurons after chronic ethanol treatment in mice. Brain Res Mol Brain Res. 121: 19-27, Tabish, M. and Ticku, MK. Alternate splice variants of mouse NR2B gene. Neurochem Int. 46: 1-9, Kalluri, HS and Ticku, MK. Regulation of ERK phosphorylation by ethanol in fetal cortical neurons. Neurochem Res. 28: , Mehta, AK., Muschweck, NM, Maeda, DY, Coop, A. and Ticku, M. K. Binding characteristics of the gamma-hydroxybutyric acid receptor antagonist [(3)H](2E)-(5- hydroxy-5, 7, 8, 9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene)ethanoic acid in the rat brain. J. Pharmacol Exp Ther. 299: , Kumari M, Ticku, MK. Regulation of NMDA receptors by ethanol. Prog Drug Res. 54:152-89, Mehta, A.K. and Ticku, M.K. An update on GABA A receptors, Brain Res. Rev. 29: , 1999 (Review). Kalluri, H.S.G. and Ticku, M.K. Potential involvement of tyrosine kinase pathway in the antagonist induced upregulation of the NMDA receptor NR2B subunit in cortical neurons, Mol. Brain Res. 65: , Mehta, A.K. and Ticku, M.K. Prevalence of the GABA A receptor assemblies containing _1-subunit in the rat cerebellum and cerebral cortex as determined by immunoprecipitation: lack of modulation by chronic ethanol administration, Mol. Brain Res. 67: , Kalluri, H.S.G. and Ticku, M.K. Effect of ethanol on phosphorylation of the NMDAR2B subunit in mouse cortical neurons, Mol. Brain Res. 68: , Mehta, A.K. and Ticku, M.K. An investigation on the role of nitric oxide in the modulation of the binding characteristics of various radioligands of GABA A receptors by 5 _-pregnan-3 -o1-20-one in the rat brain regions, Brain Res. 832: , Kumari, M. and Ticku, M.K. Ethanol differentially regulates expression of the NMDA receptor subunits at the transcriptional and post-transcriptional level. J. Neurochem. 70: ,

94 Hu, X.-J. and Ticku, M.K. Functional characterization of a kindling-like model of ethanol withdrawal in cortical cultured neurons after chronic intermittent ethanol exposure. Brain Res. 767: , Sousa, A. and Ticku, M.K. Interactions of the neurosteroid dehydroepiandrosterone sulfate with the GABA A receptor complex reveals that it may act via the picrotoxin site. J. Pharmacol. Exp. Ther. 282: , Follesa, P. and Ticku, MK. Chronic ethanol-mediated upregulation of the NMDA receptor polypeptide levels in mouse cortical neurons in culture. J. Biol. Chem. 271: ,

95 Appendix

96 EVALUATION: PHAR SPECIAL PROBLEMS STUDENT: FACULTY: SEMESTER/YEAR: Please use this form for your written evaluation of the student s work during this rotation. Each section needs a letter grade and a brief statement supporting the grade given. Criteria Grade Technical Competence Motivation Understanding of Techniques and Instrumentation Understanding of Scientific Concepts and Principles Ability to Read and Evaluate Literature Ability to Work, Think and Write Independently Overall Grade Would you consider supervising this student s Dissertation Research? If no, please provide a more detailed evaluation of this student s performance on a separate page. I have had the opportunity to review and discuss this evaluation with my faculty supervisor. Student s Signature Date A-1

97 SEMINAR SPEAKER CRITIQUE FORM Please complete the following sections to help the student speaker improve his/her presentation skills. The more detailed your comments are, the more helpful they will be to the speaker. A. Presentation Style: 1. General speaking ability: 2. Was the use of visual aids sufficient/appropriate? 3. Was the general organization of the presentation logical? 4. Was the proper amount of time devoted to each of the following? a. Introduction: b. Methodology: c. Results: d. Discussion/Conclusions: B. Knowledge of Material Did the speaker display the depth and breadth of knowledge expected for this presentation? C. Ability to Answer Questions Comment on the manner in which the speaker fielded questions. D. Ability to Interpret Experimental Results and Propose New Experiments: E. Other Comments: F. Overall Evaluation of the Presentation (circle one): Poor Average Good Very Good Excellent Name A-2 (Optional)

98 Department of Pharmacology University of Texas Health Science Center at San Antonio Petition for Oral Examination for Advancement to Ph.D. Candidacy Name of Student: Date: APPROVAL OF WRITTEN EXAMINATION (Written Proposal) Signatures of the Examination Committee: Chairman: #1 #2 #3 Outside Examiner: Typed Name Typed Name Typed Name Typed Name Typed Name / Department Signature Signature Signature Signature Signature Signatures of the committee members signify that the written proposal is satisfactory and the student may take the oral examination for advancement to Ph.D. candidacy. Return this form to the COGS Chair. A-3

99 Graduate School of Biomedical Sciences The University of Texas Health Science Center at San Antonio PETITION FOR ADMISSION TO CANDIDACY for the degree of DOCTOR OF PHILOSOPHY Name of student Graduate program GSBS Academic Record Entered program (Initial term): 19 Total no. semester hours completed: Cumulative GPA: All required courses completed: Yes No Qualifying Examinations Examinations passed: Written Date Oral Date Signatures of Qualifying Examinations Committee: Chair Research Experience Potential for productive and independent investigation substantiated by: Signature(s) of student s research advisor(s): Admission to candidacy recommended by Committee on Graduate Studies: COGS Chair Date APPROVED: Dean A-4 Date

100 DEPARTMENT OF PHARMACOLOGY TEMPORARY DISSERTATION SUPERVISORY COMMITTEE The following individuals have agreed to serve as the ad hoc Supervisory Committee for Graduate Student s Name Chair and Supervising Professor Signature (Typed Name) Department Member (Typed Name) Signature Department Member (Typed Name) Signature Department Member (Typed Name) Signature Department Outside Department Member Signature Department (Typed Name) APPROVED BY PHARMACOLOGY COGS: Chair of COGS Date A-5

101 DEPARTMENT OF PHARMACOLOGY DISSERTATION RESEARCH PROPOSAL The UTHSCSA faculty members who serve as the temporary Supervisory Committee for Graduate Student s Name have reviewed and agree to recommend approval by the Pharmacology COGS of the research proposal entitled: to be conducted in partial fulfillment of the requirements for the degree of in the graduate program in Pharmacology. SIGNATURES: Chair and Supervising Professor Signature Department (Typed Name) Member (Typed Name) Signature Department Member (Typed Name) Signature Department Member (Typed Name) Signature Department Outside Department Member Signature Department (Typed Name) APPROVED BY PHARMACOLOGY COGS: Chair of COGS Date A-6

102 Graduate School of Biomedical Sciences The University of Texas Health Science Center at San Antonio RECOMMENDATION FOR APPROVAL OF DISSERTATION RESEARCH PROPOSAL AND SUPERVISING COMMITTEE Please submit this form with a computer file containing your proposal to the Office of the Graduate Dean. The computer file should be in RTF, HTML or PDF format. (Please type all information below) Candidate Degree Program The Committee on Graduate Studies of the program has reviewed and agreed to recommend approval by the Dean of the dissertation research proposal entitled: Title of Proposal to be conducted by the above candidate in partial fulfillment of the requirements for the degree. Signatures are required for all Committee members except the External Member. By signing, you attest that you have read and approved the final version of the dissertation proposal and you agree that the proposed work is appropriate for a PhD dissertation project. Chair and Supervising Professor (please type) Dept./Rank Signature Institution Member (Program) (please type) Dept./Rank Signature Institution Member (Program) (please type) Dept./Rank Signature Institution Member (Program) (please type) Dept./Rank Signature Institution HSC Member (Outside Program) (please type) Dept./Rank Signature Institution External Member (Outside HSC) (please type) Dept./Rank (Signature not required) Institution Submitted by the Committee on Graduate Studies Signature, Chair of COGS Date Approved Signature, Associate Dean of the Graduate School of Biomedical Sciences Date A-7

103 DISSERTATION SUPERVISING COMMITTEE REPORT STUDENT: SUPERVISING PROFESSOR: DATE OF COMMITTEE MEETING: COMMITTEE MEMBERS PRESENT: The student is making satisfactory progress. 2. The student is making progress but the committee has some reservations about some aspects of the research.. 3. The committee has serious concerns about the student's research progress. Please give a brief summary of the committee's evaluation of the student's research progress for the past 6 months. If items 2 or 3 are checked, please identify the committee's concerns. PLEASE LIST ANY ABSTRACTS OR PAPERS SUBMITTED FOR PUBLICATION IN THE PAST 6 MONTHS OF WHICH THIS STUDENT IS A CO-AUTHOR: A-8

104 Graduate School of Biomedical Sciences The University of Texas Health Science Center at San Antonio REQUEST FOR FINAL DEFENSE AND ORAL EXAMINATION Submit this form to the Graduate School Dean s Office 14 days prior to the date scheduled for the Final Oral. This form should be accompanied by three (3) copies of the thesis/dissertation Abstract and Vita stapled together. Name of candidate for degree (check one) M.S. Ph.D. Title of Thesis/Dissertation The undersigned Supervising Committee 1) has judged the thesis/dissertation submitted by the candidate to be suitable for the purpose of the final oral examination 2) agrees to participate in such examination on the thesis/dissertation and other subjects which the committee may consider relevant, and 3) requests that the final oral examination be conducted on: Month, Date, Year Hour/Time Room No. (Scheduling of the room is done through Academic Scheduling, Student Services, ext Forms are provided by your department office.) Supervising Committee Chairman Department Member Department Member Department Member Department Member Department Member Department COGS Chair Date APPROVED: DEAN Date A-9

105 Graduate School of Biomedical Sciences The University of Texas Health Science Center at San Antonio REPORT ON FINAL ORAL EXAMINATION We the undersigned, as the Supervising Committee of report that we have on Date other subjects of the graduate program. examined the candidate on the dissertation and Granting of the degree of Doctor of Philosophy Recommended Not Recommended Comments: Approval of recommendation for granting of degree: By Committee on Graduate Studies in Graduate Program Chair, Committee on Graduate Studies Date By Graduate Faculty Council Dean, Graduate School of Biomedical Sciences Date A-10