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The research in this laboratory aims to better understand the biology of HBV and HCV e.g. pathogenesis of hepatitis B and hepatitis C virus associated hepatocellular carcinoma. |
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HEPATITIS & LIVER CANCER |
PROGRAM DETAILS The research in this laboratory aims to better understand the biology of HBV and HCV, with special emphasis upon elucidating the mechanism(s) of pathogenesis associated with the development of chronic liver diseases, including liver cancer. For example, the "X" protein encoded by HBV has been shown to be important for (1) supporting virus gene expression in replication, (2) for promoting the development and progression of chronic liver disease, and (3) for causing changes in gene expression within the infected liver cells that increase the risk for the development of liver cancer. X protein contributes importantly to the development of liver cancer by binding and inactivating the tumor suppressor product, p53, and several other negative growth regulatory molecules (p55sen, a senescence factor, and p21WAF1/CIP1/SDI1, another senescence factor that also inhibits cells from replicating). It is becoming clear that the release of cells from negative growth regulation is key to understanding how HBV causes cancer of the liver. X protein also blocks the ability of the immune system to directly kill virus infected cells (by blocking Fas-, TNFa- and TGFb1-mediated apoptosis), which is important in promoting chronic virus infections. As we are learning what these pathways are in greater detail, it will be possible to target X protein, or the relevant pathways themselves, to reverse these effects with drugs (i.e., chemoprevention) before tumors appear. More recent studies have identified genes whose expression is up-regulated by X protein, by using a combination of microarrays and proteomics, and it is becoming increasingly clear that these up-regulated genes stimulate hepatocellular growth and survival. Among these up-regulated genes, two appear to be novel oncogenes, one of which activates beta-catenin signaling. X protein also up-regulates the vascular endothelial growth factor receptor 3, which promotes the growth of hepatocytes. X protein also up-regulates expression of lysyl-hydroxylase, which cross-links and stabilizes collagen, inhibits expression of the TGFb1 inhibitor, alpha-2 macroglobulin, and stimulates expression of fibronectin, suggesting that the virus contributes to the development of fibrosis (scarring), which evolves into cirrhosis (a life threatening condition). This and related work is now opening up opportunities to dissect and understand the biochemical pathways involved in multi-step cancer of the liver, and points to targets for the discovery of new therapeutics. In other words, this research will permit us to devise ways to reverse the steps whereby chronic virus infection develops into liver disease and cancer. To help find drug candidates that target HBxAg, a reporter gene responsive to HBxAg trans-activation function was introduced into liver cells stably expressing HBxAg, and the system will be used for high throughput screening of compound libraries. There is also a project in the lab that aims to crystallize HBxAg with the intent of obtaining structural information that will be used for rational drug design. The pathogenesis of chronic HBV, which is a very important clinical problem, is poorly understood. Hence, the lab has created an HBV transgenic mouse which supports virus replication and develops acute or chronic liver disease under controlled conditions. This will permit the identification of immune responses that are most important for the removal of virus infected cells, and provide insights into how so many people fail to clear virus, and instead, go on to develop chronic infection, liver disease, and liver cancer. These animals are and will continue to be used to study how HBV interacts with alcohol, toxins, as well as chemicals that may accelerate the appearance of tumors, and may be used for the evaluation of potential anti-viral drugs. For example, ethanol feeding results in the stimulation of virus gene expression and replication in vivo from 10-100 fold, and anti-oxidants can reverse the effects of ethanol, suggesting that oxidative pathways are key to supporting high levels of virus in vivo. The lab has also recently demonstrated that acute, resolving hepatitis is associated with the appearance of early and strong Th1 type responses in the liver, while chronic liver disease is associated with the appearance and persistence of Th1 + Th2 type responses. This is currently providing information as to the types of immunomanipulation that potentially would convert chronic liver disease into acute, resolving hepatitis. Since 1997, the popularity of the HBV transgenic SCID mouse model has been evidenced by attracting multiple grants from NIH and 10 different contracts from industry for the preclinical evaluation of a variety of approaches against hepatitis B. The lab has also recently developed a mouse model of HBV based upon the subcutaneous transplantation of a liver cell line that produces very high levels of HBV in vivo under the regulation of tetracycline. The very high titers of virus produced (>109) is useful in rapidly assessing the strength of single and multiple drug candidates against HBV. The lab has also developed a culture system that stably replicates a full-length, infectious clone of HCV at physiologically relevant levels. This is important to study how HCV causes liver cancer, since it accelerates tumor development in the cell line in which in replicates. This system will be used as a model for both anti-viral and anti-tumor drug development. In addition, the virus in the cell line is susceptible to drugs that are known to be active against HCV (e.g., interferon), suggesting that it may become a high throughput screen for antiviral drug development as well. It is also expected that the cell line will yield genes up- and down-regulated by HCV that support virus replication and tumor formation, and that in doing so, provide new targets for anti-viral and anti-tumor drug development. These studies are currently underway. The model will also provide insights into the molecular mechanisms whereby HCV causes liver cancer. For the past 10 years, Dr. Feitelson has been technical director of a molecular diagnostics lab in microbiology. He has designed non-FDA approved tests from the research literature into tests that are clinically useful for a variety of micro-organisms, and is now performing rapid diagnostic testing by real time PCR and RT/PCR. The lab has been very active in multi- and interdisciplinary research ranging from basic science (like identifying the signal transduction pathways whereby HBV and HCV cause tumors) to translational research projects (like identifying early markers of liver cancer in the blood of chronically infected patients). The lab is now turning to apply the tools created over the years, and the insights gained from these tools, for the development of novel diagnostic and therapeutic approaches to hepatitis B and C virus infections. | |||
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BIOGRAPHY DETAILS
Mark Feitelson, Ph.D. Professor of Biology, and Associate Director, Center for Biotechnology, Temple University (USA) and Director of the Hepatitis and Liver Cancer Program at S.H.R.O attended Cypress College (Cypress, CA) from 1970-72, and then received a B.S. degree in biology from the University of California, Irvine in 1974. He received a Ph.D. in Microbiology and Immunology from the UCLA School of Medicine in 1979. His thesis presented the genetic organization of the rabbit papilloma virus. He was then an American Cancer Society postdoctoral fellow in the Department of Medicine at Stanford University from 1980-1982, where he started his work with hepatitis B virus (HBV). Dr. Feitelson was then recruited to the Fox Chase Cancer Center by Dr. Baruch Blumberg (who won the Nobel Prize for his discovery of HBV) where he continued his work in HBV. In 1988, Dr. Feitelson became an independent faculty member at the Fox Chase Cancer Center at the rank of Associate Member. In 1991, Dr. Feitelson was recruited as an Associate Professor in the Department of Pathology, Anatomy and Cell Biology at Thomas Jefferson University, and from 1997-2007 was a full-professor in the same department. He also held a secondary appointment in the Department of Microbiology and Immunology within the Kimmel Cancer Center at Jefferson. During this time, Dr. Feitelson ran a CAP certified clinical molecular diagnostic lab in microbiology for Thomas Jefferson University Hospital. Dr. Feitelson is presently Professor of Biology at Temple University and Associate Director of the Temple Biotechnology Center. He has been consistently funded by NIH and foundations since 1988 for basic science work on HBV and has attracted 10 contracts from industry for translational and applied work since 1997. Dr. Feitelson has over 100 publications in highly ranked international scientific journals, has written two books; delivered more than 160 oral presentations and/or posters at national and international scientific meetings, and has delivered more than 100 invited lectureships all over the world. In 2003, Dr. Feitelson was a visiting professor at the Center for the Study of Liver Diseases at Hong Kong University, and since then, has been named visiting professor at Fudan University (Shanghai), Guangzhou University (Guangzhou), as well as at the Second and Fourth Military Medical Universities (Shanghai and Xian, respectively) in China, where he promotes U.S./Chinese collaborations in the field of hepatitis B. Dr. Feitelson has recently been named outstanding alumnus of Cypress College. He has also served on NIH study sections, reviews manuscripts for many journals, and has mentored many students at the graduate and undergraduate levels. He is also involved in commercializing his basic science discoveries over the past 20 years in both Europe and the Far East, where hepatitis B infections and associated liver diseases are prevalent. Dr. Feitelson currently holds membership in the following scientific societies: American Association for the Advancement of Science (AAAS), American Society for Virology (ASV), New York Academy of Sciences (NYAS), American Society for Investigative Pathology (ASIP), Federation of American Societies for Experimental Biology (FASEB), American Association for Cancer Research (AACR), Association for Molecular Pathology (AMP), American Society for Microbiology (ASM)-Eastern Pennsylvania Branch and National. |
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Mark Feitelson, Ph.D. |
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