PROGRESS REPORT MEETING SCHEDULED FOR AUGUST 18 (12-4PM)

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1 research center for alcoholic liver and pancreatic diseases The Center is supported by a grant from the National Institute on Alcohol Abuse and Alcoholism, P50 AA11999 Spring 2003 A publication of the Research Center for Alcoholic Liver and Pancreatic Diseases Inside this Issue Tony Hunter Kicks Off Spring Seminar Series NIAAA Center Directors Meeting Center Offers Summer Student Fellowship Single Topic Conference on Stellate Cells with S. Friedman Spotlight Laurie DeLeve 4 th Annual Symposium Pilot Project Investigators Explore Innovative Alcohol Research Postdoctoral Fellows Recent Publications by Center Investigators CONTACTS: Hide Tsukamoto, Director htuskamo@usc.edu Anne Taguchi, Administrator ataguchi@usc.edu Fax: Web: medicine/alcohol_center Tony Hunter Kicks Off Spring Seminar Series By Hide Tsukamoto NIAAA Centers Directors Meeting Strategies to Accelerate Progress through Collaboration By Steve Pandol VA Greater Los Angeles Healthcare System/UCLA Tony Hunter, Ph.D., an internationally acclaimed scientist on oncogenic signaling at the Salk Institute kicked off the Research Center s Year 2003 Cellular Homeostasis Lecture Series with his talk, Tyrosine phosphorylation and cell signaling. Dr. Hunter s lecture attracted an audience campus-wide that packed the Doheny Auditorium to 150% of capacity. Dr. Hunter s lecture on the protein kinase complement of the human genome, highlighted the arrival of the post-genome era. Other prominent speakers who were invited to participate in the Lecture Series, included Marcus Grompe, M.D. from Oregon Health Sciences University who talked on hepatic stem cells; Mark Kay, M.D., Ph.D. from Stanford University who discussed his innovative gene therapy approaches for hemophilia and viral hepatitis; Masaru Taniguchi, M.D., Ph.D., Professor and Director of RIKEN Immunology Center in Japan who made a major contribution to identification and characterization of NKT cells; Kenjiro Wake, M.D. Emeritus Professor of Continued on page 3 Hide Tsukamoto and I attended the annual Center Directors meeting in Charleston, South Carolina, in January. The meeting was led by the new Director of NIAAA, Dr. T-K Li, and organized and hosted by Dr. Carrie Randall and the Charleston Alcohol Research Center. The major purpose of the meeting was to improve collaborative interactions among the Centers in the US. The format of the meeting was designed to ensure that leaders in each of the 18 Centers in the US develop a working relationship with other Centers for collaboration. The presentation from the Centers as well as NIAAA staff about the overall goals of the Centers Program are accessible on our Center s web site under NIAAA Centers Directors Meeting, schools/medicine/research/alcohol_center/. We learned that although each Center has unique resources and goals, in general the research of each Center falls into one of the following research disciplines. Our Center is under the category of Organ Systems/ Pathology. Genetics/ Risk Factors Organ Systems/ Pathology Treatment Neuroscience/ Drinking and Consequences Prevention/ Epidemiology Continued on page 5

2 page 2 Spotlight on By Maria Runnegar Laurie DeLeve Laurie DeLeve is Associate Professor of Medicine (Division of Gastrointestinal and Liver Diseases) at USC, a very active Member of the USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases. Although born in New York Laurie spent her childhood in Holland. She went on to study at Erasmus University of Rotterdam as an undergraduate and then as a medical student. A fellowship in Clinical Pharmacology brought Laurie to the University of Toronto in Canada. That experience reinforced Laurie s interest in basic research and led to a Ph.D. in Pharmacology followed by internship and residency at the University of Michigan. Laurie s goal was to succeed in a career that combined clinical medicine with basic research. With that aim in mind she came to UCLA to complete her clinical training with a fellowship in Gastroenterology while developing her research interests under the tutelage of Neil Kaplowitz. While in the late 80s almost everyone doing research in liver concentrated on hepatocytes, Laurie decided to focus instead on the role that other liver cells (non-parenchymal cells) play in hepatic toxicity. Laurie chose to work with sinusoidal endothelial cells (SEC). At Continued on page 3 Center Offers Lee Summer Student Fellowship In the summer of 2001, the Center instituted the Lee Summer Student Research Fellowship Program to promote involvement of undergraduate and Master s students in research on our Center s theme. The program is named after Dr. S.P. Lee who made a donation toward this noble cause. Currently there is an opportunity for 4-5 undergraduate or Master s students slots with a stipend of $500-$800 each for students interested in pursuing a summer research project. Requirements for eligibility are: Incumbent must be an undergraduate or Master s student Incumbent must be available to work full time for 8 weeks during the summer under supervision of Center member Project must be related to the pathogenesis of alcoholic liver or pancreatic diseases Incumbent must present work accomplished at the Progress Report meeting in August or our symposium in December. Interested candidates, please Anne Taguchi (ataguchi@usc.edu): Title of project Summary of project Mentor name and supporting letter (fax ) Single-Topic Conference on Stellate Cells with Scott Friedman By Hide Tsukamoto Visiting Professorship by Scott Friedman, M.D. gave us a perfect opportunity to have a single-topic mini-conference on stellate cell research on April, 3, The mini-conference was held in an informal, lab meeting style to exchange up-to-date research information among the center members who are currently engaged in research on hepatic or pancreatic fibrosis with a major interest in stellate cell biology. Andrew Melton, a Ph.D gradutate student in Dr. Hal Yee s lab at UCLA presented his research on regulation of hepatic stellate cell (HSC) contractility; Saswati Hazra, a Ph.D student in Dr. Hide Tsukamoto s lab discussed her thesis work on PPAR-gamma-mediate regulation of HSC; Hongyun She presented his findings on expression of adipogenic transcription factors and KLF-6 in HSC; Dr. Chin Sung discussed inhibition of PPAR-gamma activity by cytokines and leptin in HSC; and two Center s pilot project PIs, Drs. Aurelia Lugea and Yuan-Ping Han, presented their work on the role of plasminogen activation system in pancreatic fibrosis and regulation of matrix metalloproteinases in HSC, respectively. Lively discussions were noted among the participants throughout the conference. Insightful comments and detailed critiques made by Scott were extremely helpful for the projects presented. Moreover, the conference facilitated young scientists to interact with Scott and to directly learn from the expert.

3 page 3 Laurie DeLeve, Continued from page 2 this time very few labs were interested in these cells, so the methodology for their isolation was somewhat limited and little was known of their biochemical function. Laurie s lab was instrumental in the characterization of SEC. In the intervening years much has been learned about these cells and their contribution to the physiology and pathophysiology of liver. SECs differ from vascular endothelial cells because they lack the typical underlying basement membrane. They also have numerous pores (fenestrae) that allow direct contact between plasma and hepatocytes. Therefore SECs act as a selective barrier between blood and the rest of the liver. Because of this SECs are exposed to any toxin (including alcohol), metabolite or cytokine that reaches the liver. In the past few years Laurie s group has been studying the role of SECs in veno-occlusive disease of the liver. Veno-occlusive disease (or better called sinusoidal obstruction syndrome, SOS) occurs in response to alkaloids found in some herbal teas but most commonly in man it results from chemotherapeutic agents used in bone-marrow transplantation. Studies to determine the pathophysiology of SOS in animal models by Laurie and co-workers have shown that SECs are the primary target of the drugs, they detach resulting in the loss of sinusoidal integrity and in the obstruction of blood flow that is a hallmark of SOS. SOS is rapid and in its mild or moderate form resolves in a few days. Severe SOS will in most cases result in death. At present there is no successful treatment for SOS. But work on the role of metalloproteases with animal models of SOS in Laurie s laboratory holds promise of new therapies that will be tested very soon in clinical studies in collaboration with Dr George McDonald and his group at the Fred Hutchinson Cancer Research Center in Seattle. More recently Laurie DeLeve s research interests have turned to other aspects of SEC physiology and their role in the pathophysiology of other conditions and particularly alcoholic hepatitis (see Diagram on page 4). In 2000 Laurie received a pilot project award (Title: Non-parenchymal cell de-differentiation in alcoholic liver disease) from the USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases. In the pilot project Laurie tested the hypothesis that it is the interaction (crosstalk) between hepatocytes, hepatic stellate cells and SEC that maintains normal cell differentiation. This crosstalk would be expected to be altered in alcoholic liver disease leading to liver fibrosis. Laurie and her group showed that alcohol has a profound effect on the interactions needed to maintain normal differentiation in the liver. SECs isolated from alcohol-fed rats were found to de-differentiate in Continued on page 4 Spring Seminar Series, Continued from page 2 Anatomy and Director of Liver Research at Minophagen Phamaceutical Co. who definitively identified hepatic stellate cells as vitamin A-storing cells; Jose Mato, Ph.D., Professor of Medicine at University of Navarra, Spain, an leading authority on molecular mechanisms underlying the effects of S-adenosylmethionine; Scott Friedman, M.D., Professor and Director of Liver Research Center at Mount Sinai School of Medicine who gave an outstanding closing lecture for the Series on a novel tumor suppressor gene, KLF-6. 4 th Annual Symposium By Rosy Macias L: Dr. Wake R: Dr. Taniguchi Graduate students and postdoctoral fellows supported by the Center s institutional training program, have also taken this lecture series as a 2-unit pathology graduate course (Path 575: Frontiers of Pathology). The lectures by Tony Hunter and Jose Mato can be reviewed by visiting our Center s Web site at alcohol_center/mm.html Once again I am happy to report that our annual symposium was a great success, and we had a wonderful turnout for the all day event. Thank you to all who participated. This year s focus was on the progress made over the past 4 years and to bring to light plans for the new Center grant renewal. L-R: Dr. Jose Fernandez-Checa (Research Project 1), Dr. Sam French (Research Project 2), Dr. Hide Tsukamoto (Research Project 3) and Dr. Steve Pandol (Research Project 4) Continued on page 4

4 page 4 Laurie DeLeve, Continued from page 3 culture. This finding as well as other studies formed the basis for an R01 application: Determinants of sinusoidal endothelial cell phenotype. This project has just been funded for a four-year period by NIDDK/ NIH. Laurie is also interested in the consequences of acute injury to SECs. Other groups have shown that hepatic ischemiareperfusion injury is an important cause of organ failure after liver transplantation and that SECs are particularly sensitive to ischemia-reperfusion injury and undergo apoptotic cell death. The aim of Laurie s research is to find ways to repair damage to SECs in liver transplantation. Laurie DeLeve Current Research Influence of alcohol on non-parenchymal crosstalk The premise is that alcohol triggers changes in the interactions between non-parenchymal cells and hepatocytes. These changes may be important in the initial development of liver disease. Symposium, Continued from page 3 Acute injury to sinusoidal endothelial cells The aim of this project is to determine how injury and insults to SEC are repaired in the sinusoidal obstruction syndrome (SOS) and in liver transplant ALCOHOLIC LIVER DISEASE This two-sided approach that examines both chronic impairment of SEC function and acute injury to SECs and repair strategies will clarify the cascade of events that results in alcoholic liver disease with progression to fibrosis and cirrhosis. Laurie has just submitted to NIH an R01 grant application: Endothelial cell repair response in liver injury, which will enable her to develop new strategies to protect and preserve SEC function. Apart from the direct research interest in alcoholic liver disease Laurie s expertise with the isolation and properties of SECs has, through the Non-parenchymal Liver Cell Core, made it possible for other Alcohol Center members to incorporate SECs in their research projects. Although Laurie s research accomplishments are outstanding, she is also a first class physician with the welfare of her patients at heart. Laurie is particularly interested in drug-induced hepatotoxicity, she has written extensively and has been invited to participate in a number of panels that address this very topical problem. In addition Laurie DeLeve has held and holds many official positions in the American Association for the Study of Liver Disease (AASLD). On a personal level, tragically, Laurie lost her husband Franklin to cancer two years ago. Throughout the long difficult illness Laurie showed strength of character that we all wish we would be capable of. For those of us fortunate to work with Laurie, we know her to be funny and witty with an infectious laugh, we know her as a mother that is very proud of her beautiful and intelligent daughter Samantha. This year we again invited junior investigators, graduate students and trainees to compete for two $300 prizes for a submitted abstract (poster or oral presentation) at a national meeting on topics related to the Center's theme, "Elucidation of the mechanisms by which ethanol sensitizes and primes the liver and pancreas to diseases." The Best Abstract Award was given to Shigang Xiong and the Best Poster Award was shared by Jason Cheng and Kyung Nam. Many thanks to Drs. Chin Sung and Maria Runnegar for making some tough decisions, and congratulations to the winners! Continued on page 6 L-R: Dr. Shigang Xiong (Best Abstract Award), Jason Cheng and Kyung Nam (Best Poster Award)

5 page 5 Pilot Project Investigators Explore Innovative Alcohol Research The Center is proud to support the exploration of new directions in alcohol research. The following investigators obtained pilot project funding for Yuan-Ping Han, Ph.D. (USC) Cytokine regulation of MMPs and TIMPs by alcoholic liver The goal of this project is to understand the mechanistic pathway for the induction and activation of matrix metallo-proteinases in liver damage induced by alcohol over dosage. Joseph Reeve, Ph.D. (UCLA) Ethanol effects on PKC isoforms in the pancreas The goal of this project is to systematically determine the specific phosphorylation sites of PKC isoforms. Aurelia Lugea, Ph.D. (UCLA) Plasminogen system and alcohol-induced pancreatic fibrosis The goals of the project are to determine the effect of ethanol and its metabolites, acetaldehyde and FAEEs, on components of the plasminogen activating system in rat pacreas; to examine the consequences of plasminogen deficiency on the progression of pancreatic fibrosis, inflammation and parenchymal cell loss after ceruleaninduced pancreatitis; and to determine whether plasminogen deficiency alters the pancreatic response to ethanol after and episode of acute pancreatitis. Bruce Runyon, M.D. (Rancho Los Amigos Medical Center) A randomized, double-blind trial comparing efficacy of prednisone plus nutritional supplementation vs pentoxifylline plus nutritional supplementation in patients with severe alcoholic hepatitis The goal of this study is to compare the use of corticosteroids versus pentoxifylline in the treatment of patients with severe alcoholic hepatitis. Survival will be the primary end point of this study. Center Director s Meeting, Continued from page 1 At the meeting we discussed collaborations between Centers with the same research discipline as well as across disciplines. Plans for enhancing collaboration between Centers in each discipline are listed at the WEB site. As a result of contacts and relationships developed at the meeting, we have already initiated collaborations and are planning more. For example, Anna Gukovskaya, Steve Pandol and Hide Tsukamoto are coprincipal investigators on two research components of the Howard University application for a Developmental Center. The Pancreatic Research Group has initiated collaboration with the Emory Center to determine if alcohol alters the pulmonary injury that occurs with pancreatitis. The Emory Center has already demonstrated that alcohol in both humans and rats increases the sensitivity of the lung to injury with sepsis or trauma. Finally, we have initiated discussions with the two centers in northern California that are in the prevention/ epidemiology group. The purpose will be to enhance our own efforts in this area. The NIAAA staff is committed to enhancing the collaborations and will assist in obtaining rapid funds for small meetings and pilot projects designed to enhance collaborations. The staff also encouraged us to consider enhancing our training program by developing programs for individual trainees taking advantage of unique resources at other Center sites. The NIAAA staff will help with funds for such endeavors as well. In addition to collaboration between the Centers, the NIAAA staff strongly encouraged us to consider collaboration with industry through small business grants. According to the staff, there are very few projects submitted for their mandatory small business program and the funds go unutilized. Because of the encouragement we received for collaborative activities, we will continue to discuss opportunities and implement projects and programs using collaboration to enhance our Center s goals. Please feel free to suggest possibilities or ask for help from Hide (htsukamo@usc.edu) or Steve (stephen.pandol@ med.va.gov). New Postdoctoral Fellows Welcome to our new Postdoctoral Fellows: Brian Soreghan, Ph.D. Mentor: Austin Yang, Ph.D. Project: Mass spectrometric analysis of modified glycosyltransferases in alcoholic liver and brain injury Yan-Ling Wan, Ph.D. Mentor: Stephen J. Pandol, M.D. Project: Effects of ethanol on cell death pathways in the pancreas Other current Fellows are: Derick Han, Ph.D. (Mentor: Neil Kaplowitz, M.D.) Project: Effect of ethanol on oxidative damage to mitochondrial DNA Taunia Lee, Ph.D. (Mentor: Shelly Lu, M.D.) Project: Abnormal hepatic gene expression in methionine metabolism and reduced SAM levels in patients with alcoholic hepatitis. Mamatha Sadda, M.D. (Mentor: Shelly Lu, M.D.) Project: Regulation of Human Methionine Adenosyltransferase 2A expression by NF-kB and AP-1. Balaka Das, Ph.D. (Mentor: Dan Broek, Ph.D.) Project: Involvement of sphingosine kinase in the pathogenesis of alcoholic liver disease.

6 page 6 Symposium, Continued from page 4 At the end of the day, we all went to the Edmondson Facuty Center where we celebrated with some special guests, Dr. Donald Gracon and Donna Gracon of the American Liver Foundation: Greater Los Angeles Chapter and Jerry Reilly of Organs for Life. We also were treated to the singing of Deborah Downey. Most Recent Publications by Center Members (Dec 2002 present) Sussman S, Dent CW, Skara S, decalide P, Tsukamoto H. Alcoholic Liver Disease (ALD): A new domain for prevention efforts. Substance Use & Misuse, 37: , Lu SC, Gukovsky I, Lugea A, Reyes CN, Huang ZZ, Chen LX, Mato JM, and Pandol SJ. Role of S- adenosylmethionine in two experimental models of pancreatitis. FASEB J 17:56-8, Gukovsky I, Reyes CN, Vaquero EC, Gukovskaya AS, Pandol SJ. Curcumin ameliorates ethanol and nonethanol experimental pancreatitis. Am J Physiol 284:G85-95, Garcia-Ruiz C., Colell A., Mari M., Morales, Calvo M, Enrich C. and Fernandez-Checa JC. Defective tumor necrosis factor-a-medited hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice. J. Clin. Invest 111: , Lluis JM, Colell A., Garcia-Ruiz C, Coll O, Kaplowitz N and Fernandez-Checa JC. Acetaldehyde impairs mitochondrial glutathione transport in HepG2 cells through reticulum endoplasmic stress. Gastroenterology, 124: , PROGRESS REPORT MEETING SCHEDULED FOR AUGUST 18 (12-4PM) Pilot Project PI s, Postdoctoral Fellows and Summer Students will be presenting their progress. For more information, please contact Anne Taguchi at (323) or ataguchi@usc.edu. Research Center for Alcoholic Liver & Pancreatic Diseases Keck School of Medicine of USC 1333 San Pablo Street, MMR 4 th Floor Los Angeles, CA center