Community Seminar a Big Success

research center for alcoholic liver and pancreatic diseases cirrhosis research program The Center is supported by grants from the National Institute on Alcohol Abuse and Alcoholism, P50 AA11999, T3 AA07578 & R4AA1885 Spring 005 A publication of the Research Center for Alcoholic Liver and Pancreatic Diseases Inside this Issue 1 1 3 4 5 6 Community Seminar a Big Success Alcohol Research Center Meeting Spotlight on Aurelia Lugea Spring Seminar Series Center Welcomes Vijay Kalra Postdoc and Predoc Positions Available 6th Annual Symposium Recent Publications by Center Members Pilot Project Investigators Explore Innovative Research American Liver Foundation Liver Walk CONTACTS: Hide Tsukamoto, Director htsukamo@usc.edu 33-44-5107 Anne Taguchi, Administrator ataguchi@usc.edu 33-44-310 Fax: 33-44-316 Web: Community Seminar a Big Success By Anne Taguchi On December 4, 004, the lay public got its chance to meet the doctors involved in research on liver and pancreatic diseases as well as experts in prevention in a free seminar hosted by the Center. With attendance of about 100, this free event drew a crowd from across the Los Angeles area and included simultaneous translation for the Spanish-only speaking audience. The new Q&A format was a great success in making the panel accessible to the audience. Hosted by Jerry Reilly, CEO of Organs for Life Foundation, the audience had approximately 1.5 hours, after a 30 minute lecture, to ask any questions they had on alcohol related problems. It was an informal meeting with many questions asked from the audience. The panel consisted of USC doctors, Mimi Yu, Ph.D., Shelly Lu, M.D. and Michel Mendler, M.D.; from UCLA, Stephen Pandol, M.D., and bilingual doctor, Sammy Saab, M.D.; from the Prevention Research Center in Berkeley, Andrew Treno, Ph.D.; and from the Alcohol Research Group of the Public Health Institute, Madhabika Nayak, Ph.D. Moderator, Jerry Reilly Some examples of questions that were answered were: How much can I safely drink?, Can a social drinker get serious liver or pancreas problems?, What is it like to get a liver transplant? Continued on page 5 Alcohol Research Center Meeting By Steve Pandol VA Greater Los Angeles Healthcare System/UCLA In March of this year, the NIAAA Director, Dr. Ting-Kai Li convened his second Center Directors meeting. This one was held in San Diego. The theme of the meeting was increasing collaboration between centers in the US. Dr. Li pointed out that in the current state of flat NIH budgets, the way he feels that alcohol-related research can continue to grow is to identify and nurture collaborations between centers. Several collaborations from our Center were highlighted during the two day meeting. These collaborations include two projects with Howard University. One is on the role of liver iron in alcoholic liver disease with Hide Tsukamoto and Shigang Xiong, and the other on the effects of alcohol on cell death mechanisms in the pancreas with Steve Pandol and Anna Gukovskaya. Also, the developing collaborations with the Atlanta center were presented because evidence is emerging that processes such as alcohol-induced reactive oxygen species generation with glutathione depletion and the endoplasmic reticulum stress response occur in lung (the focus of the Atlanta group) similarly to the liver and pancreas. Finally, our collaboration Continued on page 5

page Spotlight on By Vijay Kalra Aurelia Lugea Aurelia Lugea, Ph.D. is a Research Scientist at the VA Greater Los Angeles Healthcare System and UCLA, where she is working in close collaboration and mentorship of Steve Pandol, M.D. Dr. Lugea, a native of Spain, became interested in science, thanks in part to the enthusiasm of science teachers in high school. She obtained BS and MS degree from the Department of Physiology and Nutrition of the University of Navarra, Pamplona, Spain. Here, she joined the laboratory of Dr. Francisco Ponz Ph.D.; one of the Spanish pioneers in the early 50 s conducting research concerning the mechanisms of transport of sugars and amino acids across the intestinal mucosa. Dr. Lugea studied the biochemistry and physiology of glucose and phenylalanine transporters in the enterocytes of the jejunum in rats. During her Ph.D. training, she was also engaged in teaching a course on General Animal Physiology. In 1989, after completing her Ph.D., she obtained a post-doctoral fellowship to study the antiinflammatory effects of fatty acids on the gastrointestinal mucosa, under the direction of Juan Ramon Malagelada M.D., Ph.D., who had returned from the Mayo Clinic. With Dr. Malagelada, she studied how intestinal mucus layer offered protection against noxious agents, such as Spring Seminar Series By Rosy Macias Continued on page 3 This year s Cellular Homeostasis Lecture Series was kicked off with a lecture entitled, Guarding the genome: centromeres, motors, and the mitotic checkpoint by Don Cleveland, Ph.D. of University of California, San Diego. Other prominent speakers who were invited to participate in the Lecture Series, included Makoto Suematsu, M.D., Ph.D. of Keio University in Japan who spoke on Metabolome analysis for pinpointing mechanisms for gas-mediated signal transducers ; Zena Werb, Ph.D. of University of California, San Francisco who spoke on Matrix metalloproteinases and tissue remodeling in development and pathogenesis ; Michael Karin, Ph.D. of University of California, San Diego who spoke on The IKK complex in inflammation and cancer ; Peter K. Vogt, Ph.D. of The Scripps Research Institute who spoke on Translational and transcriptional controls in PI3K- Continued on page 6 Center Welcomes Vijay Kalra By Hide Tsukamoto I am extremely pleased to announce that Dr. Vijay Kalra, Professor of Biochemistry and Molecular Biology at USC, has accepted a position of Director of Education and Training for the Research Center for Alcoholic Liver and Pancreatic Diseases. This appointment commenced on January 1 st, 005 and he will assume responsibilities of overseeing and implementing the Center s postdoctoral, graduate, and undergraduate education/ training programs. With this appointment, he will also join the Center s Executive Committee. He will bring to the center 33 years of experience in teaching medical and graduate students as well as training more than 30 postdoctoral fellows at USC. In particular, he will be instrumental in reformatting the center-sponsored Spring Lecture Series on Cellular Homeostasis (Path 575) to make it available to not only the center members but also students from different graduate programs on campus. Main topics of his outstanding research include vascular biology, inflammation, diabetes, and artherosclerosis, and they have overlapping basic science with the scientific themes of the center research. I believe that this will absolutely help promote a programmatic development in this particular research area pursued by the center investigators. Please join me in welcoming Vijay to our center. Postdoctoral and Predoctoral Fellowship Positions Available The program is supported by the Center s NIAAA Institutional Training Grant and consists of eight Training Faculty. Trainees will spend two years with the laboratory assigned to them. The selection will be made according to a match between trainee's research interests and lab. Trainees will also spend two one week sessions per year in the laboratories of Center members or Training Faculty other than their primary mentor. Candidates must have a background in biochemistry, cell biology or toxicology, and must also have American citizenship or permanent residency. Send CV and inquiry to Dr. Vijay Kalra vkalra@usc.edu or 33-44-316 (fax). For more information, see. USC is an affirmative action/equal opportunity employer.

page 3 Aurelia Lugea, Continued from page gastric acids, bile acids and infectious agents. She worked for a short time (1997-000) in a pharmaceutical industry to develop inhibitors for gastric proton pump, but passion of research drew her back to academics. In year 000, Dr. Lugea joined the laboratory of Steve Pandol, M.D., Associate Chief VA Greater Los Angeles Helathcare System in Brentwood, CA, an active investigator of USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases. Here, Aurelia studied 6 th Annual Symposium By Anne Taguchi Our symposium in December of 004, represented the first of our new 5-year funding period, and we had a wonderful turnout for the all day event. Thank you to all who participated. In addition to Fellows Balaka Das, Yan- Ling Wang and Akihiko Satoh, pilot project PI s, Ite-Laird Offringa and Aurelia Lugea, reported on their progress. Our keynote speakers were Randall T. Moon, M.D., Ph.D. who spoke on Wrnts and regeneration, and Scientific Advisory Board members, Robert McCuskey, Ph.D. and Ethanol-induced alterations of the plg system tpa upa pro-upa (-) (-) PAI-1 (+) Ethanol (+) PLASMINOGEN PLASMIN (-) Cytokine release Cell adhesion and migration Growth factor activation MMP activation fibrinolysis angiogenesis ECM degradation effects of oxidative and non-oxidative metabolites in the exocrine pancreas, particularly in acinar and the pancreatic stellate cells. Subsequently, she studied the in vivo and in vitro effects of alcohol and its metabolites on extracellular matrix-degrading proteases in the plasminogen pathway. This project was supported by a pilot project by the Center and entitled Plasminogen System and Alcohol-induced Pancreatic Fibrosis. Dr. Lugea demonstrated for the first time that following pancreas injury the plg system as a key factor in tissue repair processes. Her studies also suggested that ethanol and its metabolites exert its noxious effects at least in part by altering plasminogen activation. Based on these pilot studies, Dr. Lugea has submitted two projects to NIH. David Brenner, M.D., spoke on Ethanol binging sensitizes the liver to acetaminophen with sinusoidal endothelial cels being an early target and Hepatic fibrosis and apoptosis respectively. And once again we invited junior investigators, graduate students and trainees to compete for $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." Awards were given to Qing-gao Deng for his project entitled Non-genetic mouse model of obesity, insulin resistance and NASH, Akihiko Satoh for his project Continued on page 4

page 4 Annual Symposium, Continued from page 3 entitled Novel protein kinase C isoforms δ and ε mediate cholecystokinin-induced activation of PYK and NF-kB in pancreatic acinar cells by diverging pathways, and Yong Wu for his project entitled Mallory body formation in the primary culture of mouse hepatocytes is regulated by the integrin clustering mediated signaling pathway. Many thanks to Drs. Vijay Kalra and Maria Runnegar for making some tough decisions, and congratulations to the winners! In the evening, we all retired to the Faculty Center for a delicious meal and a string quartet from USC s Music School. Two surprise awards were given to Dr. Maria Runnegar in recognition of her hard work and contributions to the Center and to Alfonso Cardenas in celebration of his retirement and for his contributions to the Animal Core Facility. Jerry Reilly, CEO of the Organs for Life Foundation graciously hosted the reception dinner. Top Left: Dr. Steve Pandol presenting award to Dr. Maria Runnegar Top Right: Dr. Hide Tsukamoto presenting award to Al Cardenas Bottom: Group photo of symposium participants. Photo courtesy of Dean McCoy of USC s Instructional Imaging Center. Most Recent Publications by Center Members She H, Xiong S, Hazra S, and Tsukamoto H. Adipogenic transcriptional regulation of hepatic stellate cells. J Biol Chem, 80(6):4959-67, 005 Fernandez-Checa JC, Kaplowitz N. Hepatic mitochondrial glutathione: transport and role in disease and toxicity. Toxicol Appl Pharmacol. May 1;04(3):63-73, 005 Lluis JM, Morales A, Blasco C, Colell A, Mari M, Garcia-Ruiz C, Fernandez-Checa JC. Critical role of mitochondrial glutathione in the survival of hepatocytes during hypoxia. J Biol Chem. 80(5):34-3, 005 Morales A, Colell A, Mari M, Garcia-Ruiz C, Fernandez-Checa JC. Glycosphingolipids and mitochondria: role in apoptosis and disease. Glycoconj J. 0(9):579-88, 004. Fischer L, Gukovskaya AS, Young SH, Gukovsky I, Lugea A, Buechler P, Penninger JM, Friess H, Pandol SJ. Phosphatidylinositol 3-kinase regulates Ca+ signaling in pancreatic acinar cells through inhibition of sarco(endo)plasmic reticulum Ca+-ATPase. Am J Physiol Gastrointest Liver Physiol. 87(6):G100-1, 004. Bardag-Gorce F, Li J, French BA, French SW. The effect of ethanol-induced CYPE1 on proteasome activity: the role of 4-hydroxynonenal. Exp Mol Pathol.78():109-15, 005. Li J, Fu P, Deleon M, French BA, French SW. The effect of Viagra (sildenafil citrate) on liver injury caused by chronic ethanol intragastric feeding in rats. Exp Mol Pathol. 78():101-8, 005. Nan L, Wu Y, Bardag-Gorce F, Li J, French BA, Wilson LT, Khanh Nguyen S, French SW. RNA interference of VCP/p97 increases Mallory body formation. Exp Mol Pathol. 78(1):1-9, 005. Li J, Fu P, French BA, French SW. The effect of rotenone on the urinary ethanol cycle in rats fed ethanol intragastrically. Exp Mol Pathol. 77(3):10-3, 004. Li J, French B, Wu Y, Vanketesh R, Montgomery R, Bardag-Gorce F, Kitto J, French SW. Liver hypoxia and lack of recovery after reperfusion at high blood alcohol levels in the intragastric feeding model of alcohol liver disease. Exp Mol Pathol. 77(3):184-9, 004. Nan L, Wu Y, Bardag-Gorce F, Li J, French BA, Fu AN, Francis T, Vu J, French SW. p6 is involved in the mechanism of Mallory body formation. Exp Mol Pathol. 77(3):168-75, 004. Li J, French BA, Fu P, Bardag-Gorce F, French SW. Catecholamines are involved in the mechanism of the urinary alcohol level cycle in rats fed ethanol intragastrically at a constant rate. Life Sci. 75(5):3043-51, 004.

page 5 Pilot Project Investigators Explore Innovative Research The following investigators obtained pilot project funding for 005. Woojin An, Ph.D. (USC) Role of ethanol-induced histone mark for p53 function The aim this project is to study how distinct sets of histone modifications endow p53 with ability to up- or down-regulate different target genes upon ethanol-induced hepatic stress Mamoru Ishii, Ph.D. (USC) Transcriptional regulation of Msx gene by alcohol and its importance in alcoholic liver diseases The goals of the project are to determine whether Msx gene expression in hepatic stellate cells are crucial to molecular regulation of liver regeneration, and whether alcohol impairs liver regeneration via its inhibitory effects on Msx genes. Henry Lin, M.D. (USC) Endotoxemia and liver injury in alcoholic liver disease The goal of this study is to determine whether small intestinal bacterial overgrowth may be the source of endotoxemia and contribute to liver injury in alcoholic liver disease. Kasper Wang (Children s Hospital Los Angeles) Role of FGF10 in liver organogenesis and regeneration The aims of the study are to determine whether FGF10 is involved in the proliferation and differentiation of hepatocytes and biliary epithelium from the budding foregut endoderm, and whether FGF10 is involved in the repair process of the liver in response to injury and that this response is impaired during ethanol ingestion. Alcohol Research Center Meeting, Continued from page 1 With the Berkeley group on community intervention was presented to show how centers with disparate skills can develop fruitful collaborations. Other topics of great interest to NIAAA were presented in order to increase our awareness of the Institute s strategic plan and resources to implement the plan. These include interests in drug development for treatment of alcoholrelated disorders including vaccines. Examples of vaccine development projects for cocaine and nicotine were presented to illustrate the possibility. Also of significant interest to the Institute are the identification of biomarkers and biosensors for better identification of individuals with alcohol-related disorders. Continued on page 6 Our next Community Seminar is on December 3, 005 Our Annual Symposium is on November 18, 005 Community Seminar, Continued from page 1 With Los Angeles County having high incidence of alcoholic liver disease (8 th leading cause of medical death) compared to the rest of the country (10 th leading cause of death) and with high risk groups (Hispanic males for ALD and African Americans for pancreatitis), populating the Los Angeles area, we were very glad to see excellent audience participation with challenging questions that elicited very interesting discussions. With the success of this event, we plan on offering a Community Seminar annually. Our goals are to attract more of the demographics that these diseases affect so that they may have access to our panel of experts and ask questions. Our Center is committed to promoting prevention and treatment of these diseases. To this end, there is an exciting collaborative development occurring with another NIAAA-funded Alcohol Research Center, the Prevention Research Center in Berkeley, CA. The two Centers are planning a pre-intervention research proposal to reduce risks of liver disease in an at-risk population. Still in planning stages, the proposal will: (1) address environmental contexts by locating at-risk neighborhoods; () survey the risk factors, including indications of liver disease as well as survey the context of risk behavior to identify who, where, what for intervention; and (3) utilize neighborhood community support groups, and focus groups to elicit suggestions regarding potential interventions to address risk factors that have been identified in each neighborhood and to assess the extent to which there is consensus and support for taking action. Please be sure to view the video from the event at our website. Panel members answer audience questions. This event would not have been possible were it not for the generous donation of translations headsets by the Boyle Heights Neighborhood Council and the City of Los Angeles. Thanks are also due to Rosendo Hernandez, Marco Perez, as well as Fisher Scientific International, Bristol-Myers Squibb Company, Gilead Sciences, Roche Laboratories Inc., Shering Plough Corporation for their support.

page 6 Spring Seminars, Continued from page dependent oncogenesis ; Gordon C. Shore, Ph.D. of McGill Univeristy who spoke on Regulation of oncogene-driven apoptosis by BCL- family proteins. Therapeutic opportunities ; Didier Y. R. Stainier, Ph.D. of the University of California, San Francisco who spoke on Endodermal organ development in zebrafish ; Yohsuke Mukouyama, Ph.D. of Cal Tech who spoke on Nerve-blood vessel interactions: How nerves control vessel identity and branching pattern ; Punam Malik, M.D. of Children s Hospital who spoke on Gene therapy of hematological diseases and Yuan-Ping Han, Ph.D. of USC who spoke on Inflammation induced trans-differentiation of hepatic stellate cells in 3D ECM. Graduate students and postdoctoral fellows supported by the Center s institutional training program, have also taken this lecture series as a -unit pathology graduate course (Pathology 575: Frontiers of Pathology). Opening speaker, Dr. Don Cleveland of UCSD The seminar series has been met with wonderful positive feedback and we look forward to offering another fantastic series in 006 Join in the fun at the American Liver Foundation s 7th Annual Liver Walk and fun run on June 4, 005. This popular family event raises funds for the serious task of researching a cure for hepatitis and other liver diseases. Griffith Park is again the setting for this fundraiser that depends on walkers and runners to collect as many sponsor dollars as they can. Many of the participants form teams composed of friends, family and co-workers, donning team t-shirts and proudly displaying team banners. Held in the Merry-Go-Round area of the park, check in and registration will start at 6:30 a.m., with the official start of the 5K Run and 5K Walk set for 8 a.m. At 9:00 a.m. a shorter 1.5 Turtle Walk will begin. Awards and prizes will be distributed before the event ends at noon. Every registered participant receives a t-shirt, and other prizes depending on the amount raised. Participants will also have their name submitted into a special drawing for each $50 in pledge money collected. The cost to pre- register for the Run/Walk is $5 and $30 on the day of the event. For further information or to register, visit www.liver411.org, or call Pam Brady at 310.670.464. Alcohol Research Center Meeting, Continued from page 5 Because of the importance of continuing to identify and pursue collaborations between centers, we are organizing a meeting in Santa Barbara on June 6 during the annual RSA meeting. This meeting will focus on the identification of common alcohol-induced processes in lung, liver and pancreas so that we can share expertise in order to expedite discovery for treatment of organ injury disorders related to alcohol. For information about this meeting, please contact Ms. Yoon Jung at yoon.jung@med.va.gov or (310) 68-3676. Research Center for Alcoholic Liver and Pancreatic Diseases Keck School of Medicine of the 1333 San Pablo Street, MMR 4 th Floor Los Angeles, CA 90033