BETARETROVIRUS PATHOGENESIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 逆转录病毒是包括白血病(HTLV)和艾滋病(HIV)在内的几种人类疾病的已知病原体。另一种逆转录病毒，小鼠乳腺肿瘤病毒(MMTV)，长期以来一直被怀疑在人类疾病中发挥作用，特别是乳腺癌。这部分归因于它在小鼠身上诱发癌症的能力，部分归因于在许多人类乳腺肿瘤中存在相关序列。MMTV现在与另一种人类疾病--原发性胆汁性肝硬变(PBC)有关，在这种情况下被称为人类贝塔病毒(HBRV)。PBC是一种慢性肝病，肝内胆管被破坏，导致胆汁酸积聚，最终导致肝功能衰竭。PBC患者的胆管上皮细胞(BEC)表现出特有的线粒体抗原的质膜表达，这可能解释了PBC患者中独特存在某些抗线粒体抗体(AMA)以及由此导致的破坏胆管的炎症反应。用患者标本条件培养液和鼠源性MMTV均能诱导正常BEC表面表达主要线粒体抗原丙酮酸脱氢酶-E2(PDC-E2)。利用PBC的体外模型，我们将利用最先进的基因组和蛋白质组学技术来研究PBC发病的分子机制。从科布雷资助的这个项目中获得的介导病理的细胞基因的鉴定，将随后导致对病毒诱导的PBC发病机制中所涉及的细胞途径的表征，以及对如何逆转或防止其诱导的洞察。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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.