This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Retroviruses are the known etiologic agents of several human diseases including leukemia (HTLV) and AIDS (HIV). Another retrovirus, mouse mammary tumor virus (MMTV), has long been suspected of playing a role in human disease, specifically breast cancer. This is due partly to its ability to induce cancer in mice and partly to the presence of related sequences in many human breast tumors. MMTV has now been linked to another human disease, Primary Biliary Cirrhosis (PBC), and has been termed the Human betaretrovirus (HBRV) in this context. PBC is a chronic disease of the liver whereby the intrahepatic bile ducts are destroyed leading to accumulation of bile acids and ultimately to liver failure. Biliary epithelial cells (BEC) from PBC patients display a characteristic plasma membrane expression of mitochondrial antigens, which may explain the unique presence of certain anti-mitochondrial antibodies (AMA) in PBC patients and the resulting inflammatory response that destroys the bile ducts. Surface expression of the major mitochondrial antigen pyruvate dehydrogenase-E2 (PDC-E2) can be induced in cultured normal BEC when inoculated with both patient-sample conditioned medium and with mouse derived MMTV. Using this in vitro model of PBC we will investigate the molecular mechanisms behind the pathogenesis by state of the art genomic and proteomic techniques. Identification of the cellular genes that mediate pathology gained from this COBRE-funded project will then lead to a subsequent characterization of the cellular pathways involved in the virally induced pathogenesis of PBC and insights into how to reverse or prevent their induction.
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