BETARETROVIRUS PATHOGENESIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。逆转录病毒是几种人类疾病的已知病原体，包括白血病（HTLV）和艾滋病（HIV）。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，特别是乳腺癌中发挥作用。这部分是由于它在小鼠中诱导癌症的能力，部分是由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——原发性胆汁性肝硬化（PBC）有关，并在此背景下被称为人类β逆转录病毒（HBRV）。PBC是一种慢性肝脏疾病，肝内胆管被破坏，导致胆汁酸积聚，最终导致肝功能衰竭。PBC患者的胆道上皮细胞（BEC）显示出线粒体抗原的特征性质膜表达，这可能解释了PBC患者中某些抗线粒体抗体（AMA）的独特存在以及由此产生的破坏胆管的炎症反应。在培养的正常BEC中，用患者样本条件培养基和小鼠源性MMTV接种均可诱导线粒体主要抗原丙酮酸脱氢酶e2 （PDC-E2）的表面表达。利用这种体外PBC模型，我们将通过最先进的基因组学和蛋白质组学技术研究其发病机制背后的分子机制。从cobre资助的项目中获得的介导病理的细胞基因的鉴定将导致随后对病毒诱导的PBC发病机制中涉及的细胞途径的表征，并深入了解如何逆转或预防其诱导。

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.