PS121: Disease Mechanisms and Therapies Crosbie-Watson (4 units)
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1 1 PS121: Disease Mechanisms and Therapies Crosbie-Watson (4 units) LECTURE COURSE INSTRUCTOR TEACHING ASSOCIATE DISCUSSION SECTIONS VIDEO AND AUDIO REQUIRED READINGS GRADING FACULTY COMMITMENT COURSE POLICIES ATTENDANCE REQUIRED 1 hour 15 mins lecture; 1 hour discussion TR 8:00 to 9:15 AM; LaKretz 120 Rachelle H. Crosbie-Watson, Ph.D. Professor of Integrative Biology and Physiology; Professor of Neurology Education Liaison, UCLA Center for Duchenne Muscular Dystrophy Terasaki Life Sciences Building (TLSB) Tel: rcrosbie@physci.ucla.edu Office hours in TSLB 1121: Tues. 9:15am to 10am Fri. 3pm to 4pm and anytime after class! TBA ATTENDANCE REQUIRED Mon Fri 10am to 10:50am LaKretz 100, Section 1A 4pm to 4:50pm LaKretz 101, Section 1B Lectures will be audio-recorded. Please use the following link: For tech issues, contact Bruincast: bruincasthelp@ucla.edu Assigned primary articles and review articles from the current scientific literature. Readings can be downloaded from the Life Sciences Moodle website or through your MyUCLA account. It is strongly suggested that reading materials are printed in color to view experimental data. Grading based upon scores earned on: 8 quizzes (25 points each) 1 participation score (50 points) 2 midterms (100 points each) on the lecture material 1 final comprehensive exam (200 points) Total points: 650 points The scientists, physicians, physical therapists, families, and members of the disabled community make significant (and completely voluntary) contributions to this course because they deeply value educating students in disease mechanisms and therapies. Their investment is what makes this a truly unique undergraduate experience. Enjoy! All quizzes, midterms, and the final are closed book. There are no make-up midterms or quizzes. If you feel that a clerical error or oversight was made in the grading of your midterm/quiz, please submit
2 2 COURSE OBJECTIVES your request with a cover letter detailing a written explanation within 7 calendar days to the TA. At the end of the course, students should be able to: 1. Understand complex molecular and cellular mechanisms of disease 2. Design personal medicine approaches aimed at correcting genetic mutations 3. Critically evaluate current scientific research 4. Create a scientific abstract to reflect findings from experimental research 5. Design experiments to support a hypothesis or to support a scientific conclusion 6. Design and interpret pre-clinical trials/data from animal models 7. Evaluate pre-clinical outcome measures 8. Interpret data from diagnostic tests and evaluate the strengths and weaknesses of these tests 9. Appreciate the complex social effects of life-threating illnesses on families and communities 10. Evaluate ethical issues pertaining to biomedical research 11. Identify and evaluate the financial conflicts regarding biopharmaceutical research 12. Track and correlate biotech stock prices as they relate to clinical trial data CATALOG DESCRIPTION INTRODUCTION TO DMD The proposed course will reveal the etiology and pathogenesis of Duchenne muscular dystrophy and will highlight some of the fundamental scientific discoveries using original scientific research. Therapies aimed at individual stages of disease will be explored as a method to develop critical, expert-like thinking skills. Lectures will be based on experiments from primary scientific literature and students will be expected to understand genetic and phenotypic animal models of muscular dystrophy, design experiments, and predict outcomes from research data. Many approaches will be used to convey the human aspect of disease including films, poems, readings as well as panel discussions with families affected by DMD, physicians specializing in DMD treatment, and scientists. Duchenne muscular dystrophy (DMD) is an inherited muscle wasting disorder. This disorder affects skeletal and cardiac muscle and is the most common lethal genetic disorder in children. In spite of the relative anonymity of this disease, many pioneering genetic discoveries have had a basis in Duchenne including the first example of positional cloning, some of the earliest viral vector mediated gene delivery and some of the first stem cell transplantations into humans. Duchenne therapies continue to lead the way in personalized genetic medicine, with two novel therapies targeting cellular splicing machinery and nonsense-mediated
3 3 suppression. The proposed course will reveal the etiology and pathogenesis of Duchenne muscular dystrophy and will highlight some of these fundamental scientific findings. Alterations in the cellular cytoskeleton and/or modulation of intracellular signaling patterns are often manifested in changes in normal cellular function, and these changes are in turn reflected in muscle disease. THERAPIES FOR DMD DARIUS GOES WEST FILM The progressive developments of muscular dystrophy will be discussed in terms of structure/function alterations cell, and changes in the regulation of intracellular interactions. Therapies aimed at individual stages of pathogenetic disease will be explored as a method to develop critical, expert-like thinking skills. Lectures will be based on experiments from primary scientific literature that reveal new biological findings related to disease. Students will be expected to understand genetic and phenotypic animal models of muscular dystrophy, design experiments, and predict outcomes from research data. Other, non-muscle diseases (cancer, viral infections) that affect dystrophin will be presented. The course will explore how information gained from investigation of muscular dystrophy can be applied to these disorders. It is expected that an indepth investigation of DMD will ready students for rigorous, meaningful understanding of other disorders since DMD shares pathogenetic mechanisms with a wide range of human diseases. Because one third of the mutations in the dystrophin gene are spontaneous, this disease will always be present in the population. Lessons about this disease transcend genetics and provide life lessons about courage, perseverance, and friendship. In this course, students will learn about the documentary Darius Goes West which portrays a young man, Darius, who has Duchenne muscular dystrophy and who watched his older brother die from the same disease. The film documents Darius journey across America with his crew in hopes of having MTV pimp his ride. In this case, Darius ride is his wheelchair. Along the way, the crew develops meaningful relationships while drawing attention to challenges faced by the disabled in our country. READINGS FROM THE COLLECTED WORKS OF AMERICAN POET MATTHEW MATTIE STEPANEK whose six books of poetry and one book of essays reached The New York Times bestsellers list. Mattie experienced the premature deaths of his three older siblings; and Mattie himself died from muscular dystrophy at the age of 13. During his life, Mattie was an advocate for peace and lobbied Congress on behalf children with life-threatening illnesses. Maddie s poetry focuses on the beauty and happiness in the world. From our discussions, students have an appreciation of the human side of disease and what it means to live with a progressive, life-threatening disability in America.
4 4 WEEK 0: INTRODUCTION TO COURSE 1. Muscle Physiology Chapter 8 from Sherwood Human Physiology: From Cells to Systems à Thursday, September 26, 2013 (LECTURE 1) Instructor: Professor Rachelle Crosbie-Watson, Ph.D., Education Liaison of the Center for Duchenne Muscular Dystrophy (CDMD) 1. Introduction to the Course Introduction of Brian McMorran, Teaching Assistant Objectives, syllabus, evaluation criteria, discussion sections Discussion of teaching philosophy based on research by C. Wieman, Ph.D. (Nobel Laureate) Watch a documentary film Darius Goes West, documentary film about a young man living with DMD This is a documentary about a young man, Darius, with DMD who travels across America with his crew in an old van so that Darius can fulfill his wish to touch the Pacific Ocean. Along the way, they lobby MTV to pimp out Darius ride, which is his wheelchair. The film reveals struggles of coping with a life-threatening illness. Darius watched his older brother die from the same disease. We will also learn what it means to be disabled in America. WEEK 1: INTRODUCTION TO MUSCLE PATHOLOGY 1. Dystrophin and Muscular Dystrophy: Past, Present, and Future O Brian and Kunkel (2001) Mol. Genet. Met. 74, Watch interview with Darius Weems on ABC Dateline (2012). Link available on Moodle. à Tuesday, October 1, 2013 (LECTURE 2) COMPLETE DGW FILM. Dr. Crosbie-Watson is at World Muscle Society Meeting. à Lecture 3 (Thursday, October 3, 2013) Guest Instructor: Professor Négar Khanlou, M.D., Dept. Pathology and Laboratory Medicine What Traditional Muscle Histology Can Tell Us About Muscle Diseases Muscle Pathology Histological analysis of muscle biopsy sections from normal controls and Duchenne patients and other muscle disorders. This lecture was kindly facilitated by Professor Linda Baum, M.D., Ph.D., Director of Clinical Laboratory Medicine (Pathology).
5 5 WEEK 2: INTRODUCTION TO DYSTROPHIN GENETICS; UCLA DISABILITY HISTORY AND AWARENESS WEEK Readings: All readings, articles, and information have been posted on Moodle. 1. Watch documentary film: Dusty s Trail: Summit to Borneo. Oct 8th (Tuesday), at 6:30pm in De Neve Learning Auditorium. Discussion panel with Dusty, film crew, scientists, parent advocates. 2. O Brien and Kunkel (2001) Dystrophin and Muscular Dystrophy: Past, Present, Future Mol. Genet. Met. 74, An Interview with Lou Kunkel (2009) Nature Reviews. 4. Kunkel (2005) Cloning of the DMD Gene Am. J. Hum. Genet. 76: à Lecture 4 (Tuesday, October 8, 2013) Instructor: Professor Rachelle Crosbie-Watson, Ph.D., Education Liaison of the CDMD Using Mechanisms and Therapies of Disease to Teach Advanced, Critical Thinking Skills Introduction and Review of Skeletal Muscle Physiology Electron microscopy of skeletal muscle, neuromuscular junction structure Membrane structures in muscle that are key to regulating voltage transmission and calcium release Lateral and longitudinal forces exerted on muscle during contraction Introduction to Duchenne Muscular Dystrophy (DMD) History, mode of inheritance, clinical features, pseudohypertrophy, Gower s Sign Video presentation of DMD progression Brief introduction to muscle histopathology Introduction to dystrophin as DMD disease gene à Lecture 5 (Thursday, October 10, 2013) Guest Instructor: Professor Stanley Nelson, M.D., Dept. Human Genetics (UCLA), Co- Director of CDMD Discovering the Dystrophin Gene Today Compared to 1986: the Revolution in Molecular Genetics Discovery of dystrophin as the disease gene that causes DMD by Louis Kunkel, Ph.D. (Harvard) Chromosome walking as methodology to discover dystrophin gene Modern approaches to dystrophin mutation analysis: exome sequencing WEEK 3: EXON SKIPPING THERAPIES TO RESTORE DYSTROPHIN FUNCTION; DYSTROPHIN PROTEIN AS A PROTECTOR OF THE SARCOLEMMA 1. Repair or replace? Exploiting novel gene and cell therapy strategies for muscular dystrophy. Benedetti, S., Hoshiya, H., Tedesco, F. FEBS J. 2013, epub. Review. 2. Dantrolene enhances antisense-mediated exon skipping in human and mouse models of Duchenne muscular dystrophy. Kendall GC, Mokhonova EI, Moran M, Sejbuk NE, Wang DW, Silva O, Wang RT, Martinez L, Lu QL, Damoiseaux R, Spencer MJ, Nelson SF, Miceli MC.
6 6 (2012) Dec 12;4(164): Gene Therapy with a Difference New York Times article, Sept. 24, Ervasti, J.M. and Campbell, K.P. Membrane Organization of the Dystrophin-Glycoprotein Complex (1991) 66: à Lecture 6 (Tuesday, October 15, 2013) Guest Instructor: Professor M. Carrie Miceli, Ph.D., Dept. Molecular Biology, Immunology, and Molecular Genetics (UCLA), Co-Director of CDMD Can Personalized Medicine Correct the Primary Genetic DMD Defect? Leveraging the Muscle Cell s RNA Splicing Machinery to Induce Exon Skipping Introduction to mechanism of exon skipping approach Limitations of exon skipping therapies as a treatment for DMD (efficiency, treatment costs, broad applicability) Research approaches to address limitations of exon skipping therapies Clinical trail data (Serepta/GSK) and effects on the stock market à Lecture 7 (Thursday, October 17, 2013) Instructor: Professor Rachelle Crosbie-Watson, Ph.D. Identifying Dystrophin-associated Proteins Using Traditional Protein Biochemistry that Serendipitously Reveals Numerous New Disease Genes 1. Using Animal Models to Design Preclinical Trials to Test Therapeutics for DMD Case Study Presentation & Discussion of Clinical Trial Data with AON therapy Video to illustrate significant improvements in Golden Retriever s mobility after AON treatment 2. Introduction to Dystrophin Protein Structure & Function Dystrophin localization within muscle Protein interaction domains 3. Loss of Dystrophin Protein in DMD Causes Sarcolemma Membrane Damage 4. Introduction of the Dystrophin-Glycoprotein Complex WEEK 4: INTRODUCTION TO MOUSE MODELS OF DMD: ROLE IN PRE-CLINICAL TRIALS 1. Mammalian animal models for Duchenne muscular dystrophy. Willmann R, Possekel S, Dubach-Powell J, Meier T, Ruegg MA. Neuromuscul Disord Apr;19(4): Review. 2. Ervasti JM, Ohlendieck K, Kahl SD, Gaver MG, Campbell KP. Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle. Nature. (1990) 345: Matsumura K, Ervasti JM, Ohlendieck K, Kahl SD, Campbell KP. Association of dystrophinrelated protein with dystrophin-associated proteins in mdx mouse muscle. Nature : Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy. Grady RM, Teng H, Nichol MC, Cunningham JC, Wilkinson RS, Sanes JR. (1997) Cell. 90:
7 7 à Lecture 8 (Tuesday, October 22, 2013) Instructor: Rachelle Crosbie-Watson, Ph.D. Exploiting Gene Regulation Mechanisms for Therapy: Making Use of the Cell s Own Defenses Utrophin-based Therapy: Taking Advantage of Compensation Mechanisms Utrophin expression at the neuromuscular junction in normal muscle Utrophin is increased in DMD Introduction of utrophin ameliorates DMD in mice à Lecture 9 (Thursday, October 24, 2013) Instructor: Rachelle Crosbie-Watson, Ph.D. How Small Molecular Events like Gene Mutations Affect Cells and Tissues 1. Adaptive Responses of Muscle Hyperplasia and hypertrophy Reversible and irreversible cell damage Cellular adaptations in muscular dystrophy (hypertrophy, regeneration, necrosis) 2. Introduction to Mouse Models of Duchenne Muscular Dystrophy Naturally occurring mouse models of DMD: mdx mouse Genetically engineered mouse models of DMD Genotypic vs. phenotypic mouse models of DMD WEEK 5: ROLE OF IMMUNE CELLS IN DMD DISEASE PATHOLOGY 1. Immunological Components of Genetically Inherited Muscular Dystrophies: Duchenne Muscular Dystrophy and Limb-Girdle Muscular Dystrophy Type 2B Spencer MJ, Kramerova, I, Miceli, MC, Nagaraju, K. Skeletal Muscle, in press. à Lecture 10 (Tuesday, October 29, 2013) MIDTERM #1. à Lecture 11 (Thursday, October 31, 2013) Guest Instructor: Professor Melissa Spencer, Ph.D., Dept. Neurology (UCLA), co-director of CDMD Inflammation: Friend or Foe? 1. Inflammation in DMD Muscle Role of macrophages in dystrophic muscle How inflammation and fibrosis are connected: a common therapeutic target? What signals inflammation in muscle? Detection of inflammatory cells in muscle 2. Clinical Approaches to Decrease Inflammation Steroids: effects on inflammation?
8 8 WEEK 6: MODULATORS OF MUSCLE GROWTH AND REGENERATION: TARGETS FOR THERAPY 1. Concise review: stem cell therapy for muscular dystrophies. Wilschut KJ, Ling VB, Bernstein HS. Stem Cells Transl Med Nov;1(11): à Lecture 12 (Tuesday, November 5, 2013) Instructor: Professor Rachelle Crosbie-Watson, Ph.D. Observing the Absurd: Are Double-Muscled Cattle Telling Us How to Treat Disease? Regulation of Muscle Mass: Myostatin Case Study: Myostatin Treatment Ameliorates Muscular Dystrophy in Many Animal Models Myostatin mutations in cattle, canines, and humans Loss of myostatin improves Mdx mouse pathology Myostatin inhibition with antibodies to myostatin à Lecture 13 (Thursday, November 7, 2013) Guest Instructor: Professor April Pyle, Ph.D., Dept. Microbiology, Immunology, and Molecular Genetics (UCLA) How to Chose Your Favorite Stem Cell! Using Stem Cell Therapies as a Novel Treatment for DMD 1. Introduction to Stem Cell Therapy Definition and properties of muscle stem cells Role of stem cells in self-renewal and muscle regeneration Exhaustion of stem cells in DMD 2. Approaches to isolate of muscle stem cells Treatment of mouse models of muscular dystrophy with stem cells WEEK 7: BLOOD FLOW REGULATION IN DMD MUSCLE: PRECLINICAL AND CLINICAL TRIALS TARGETING THE NOS PATHWAY 1. Treatment with a nitric oxide-donating NSAID alleviates functional muscle ischemia in the mouse model of Duchenne muscular dystrophy. Thomas GD, Ye J, De Nardi C, Monopoli A, Ongini E, Victor RG. PLoS One. 2012;7(11):e Tadalafil alleviates muscle ischemia in patients with Becker muscular dystrophy. Martin EA, Barresi R, Byrne BJ, Tsimerinov EI, Scott BL, Walker AE, Gurudevan SV, Anene F, Elashoff RM, Thomas GD, Victor RG. Sci Transl Med Nov 28;4(162):162ra155. à Lecture 14 (Tuesday, November 12, 2013) Instructor: Professor Rachelle Crosbie-Watson, Ph.D. Sleuthing Molecules That Improve Blood Flow to Muscle Revisiting the vascular hypothesis of DMD Localization of nnos in normal and DMD muscle Loss of nnos causes muscle ischemia during exercise Strategies to restore nnos activity in mdx mice
9 9 à Lecture 15 (Thursday, November 14, 2013) Guest Instructor: Professor Ron Victor, M.D., Department of Medicine (UCLA); Director, Hypertension Center of Excellence; Associate Director, Cedars-Sinai Heart Institute Viagra/Cialis Boost Cell Signaling Activity, But Can They Address Muscle Ischemia and Vascular Dysfunction in DMD? Rationale for use of tadalafil Experimental design to measure blood flow during exercise Recruitment of patients Outcomes and future studies: Role of Pfizer in current clinical trials WEEK 8: PHYSICAL THERAPY AND GAIT ASSESSMENT IN DMD: OUTCOME MEASURES FOR CLINICAL TRIALS; FDA REGULATION OF CLINICAL TRIALS 1. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, Kaul A, Kinnett K, McDonald C, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C; DMD Care Considerations Working Group. Lancet Neurol. (2010) 9: Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, Kaul A, Kinnett K, McDonald C, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C; DMD Care Considerations Working Group. Lancet Neurol. (2010) 9: à Lecture 16 (Tuesday, November 19, 2013) Guest Instructor: Professor Eileen Fowler, Ph.D., P.T., Dept. Orthopedic Surgery (UCLA) Using Avatar Technology to Advance Clinical Outcomes for Muscle Diseases Biomechanical Analysis of Gait in Individuals with Duchenne Muscular Dystrophy: Results from Clinical Trials Physical therapy tools for DMD Clinical outcome assessments for DMD (gait analysis, 6-min walk test) Discussion for global assessment tool in clinical trails The role of parent education in disease management and treatment à Lecture 18 (Thursday, November 21, 2013) Guest Instructors: Professor Perry Shieh, M.D. Ph.D., Dept. of Medicine, UCLA Patient Treatment Modalities and Clinical Trials Professor Linda Baum, M.D. Ph.D. Dept. of Pathology and Laboratory Medicine, UCLA Glycobiology and Laminin-Binding Impact Disease WEEK 9: PANEL DISCUSSION WITH FAMILIES AND SCIENTISTS
10 10 1. Key concepts of clinical trials: a narrative review. Umscheid CA, Margolis DJ, Grossman CE. Postgrad Med Sep;123(5): à Lecture 19 (Tuesday, November 26, 2013) Discussion panel. This lesson will NOT be video or audio recorded. All recording and photographic devices strictly prohibited. Guest Panelists will include families affected by DMD, scientists, physicians, activists The parents that will be joining us in class have also significantly contributed to efforts to Duchenne research and awareness. They have started fund raising organizations, research centers of excellence, and contributed to documentaries and short videos on DMD. à Thursday, November 28, 2013 THANKSGIVING HOLIDAY! NO CLASS WEEK 10: CARDIOMYOPATHY IN DMD à Lecture 20 (December, 3, 2013) Instructor: Professor Andrew D. Watson, M.D. Ph.D. Dept. of Medicine Cardiomyopathy in Muscular Dystrophy: From Molecular Mechanisms to Physiology to Treatment Approaches Cardiac and pulmonary function in normal and stressed states Role of calcium regulation in function Congestive heart failure and drug interventions aimed at signaling pathways à Lecture 21 (December 5, 2013) MIDTERM #2.
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