Immunologic Mechanism/Destruction/Biliary Artesia

描述（由申请人提供） 我的职业目标是成为一名医生科学家， 肝脏疾病和作出重大的研究贡献的领域 儿科肝病学。我对胆道闭锁（BA）及其 可能的发病机制，因为我接触到这种疾病， 儿科住院医师在过去的一年里，我一直在学习免疫学， 西北大学Stephen米勒博士的实验室。我计划 作为一名研究科学家长期留在学术环境中，目标是 明确定义免疫系统在疾病发病机制中的作用 胆道闭锁和其他儿科肝病。 胆道闭锁是一种婴儿期进行性炎症性胆管病， 导致肝外和肝内的纤维化和闭塞 胆管免疫反应似乎是正在进行的 胆管的破坏。这里的假设是， 病毒诱导的进行性自身反应性CD 4 + Th 1细胞介导的 胆管的破坏A组轮状病毒鼠模型将用于 测试这一假设，并需要一个病毒诱导的，进行性炎症 肝外和肝内胆管破坏导致肝外 导管纤维化和闭塞。对人体肝脏组织的有限研究 还将进行BA诊断时获得的检查。具体目标1 将是在这个小鼠模型中表征炎症免疫反应 通过免疫组织化学和流式细胞术研究。 还将进行细胞因子谱的表征。具体目标2 将决定导管破坏的主要介质（病毒与 免疫应答），通过比较感染的BALB/c幼仔与 感染的SCID（免疫缺陷）幼崽。具体目标3将确定是否 在小鼠模型中存在对胆管抗原的自身反应性淋巴细胞 通过进行体外T细胞增殖研究。具体目标4将 表征人肝组织中的炎性免疫应答， 免疫组化检查诊断BA的时间。细胞因子 谱的特征在于细胞因子mRNA表达。

DESCRIPTION (provided by applicant) My career goals are to become a physician scientist, caring for children with liver disease and making significant research contributions to the field of Pediatric Hepatology. I have been intrigued with biliary atresia (BA) and its possible mechanisms of pathogenesis since my exposure to this disease in pediatric residency. For the past year, I have been studying immunology in the laboratory of Dr. Stephen Miller, PhD, Northwestern University. I plan to remain in the academic setting long-term as a research scientist with the goal of defining clearly the role of the immune system in the pathogenesis of biliary atresia and other pediatric liver diseases. Biliary atresia is a progressive, inflammatory cholangiopathy of infancy that leads to fibrosis and obliteration of both the extrahepatic and intrahepatic bile ducts. The immune response appears to be the key player in the ongoing destruction of the bile ducts. The hypothesis herein is that the pathogenesis of BA involves a viral induced, progressive autoreactive CD4+ Th1 cell mediated destruction of bile ducts. The group A rotavirus murine model will be used to test this hypothesis and entails a virally induced, progressive inflammatory destruction of extrahepatic and intrahepatic bile ducts leading to extrahepatic ductal fibrosis and obliteration. Limited studies on human liver tissue obtained at the time of diagnosis of BA will also be performed. Specific Aim 1 will be to characterize the inflammatory immune response in this murine model through the use of immunohistochemistry and flow cytometric studies. Characterization of the cytokine profile will also be performed. Specific Aim 2 will determine the principal mediator of ductal destruction (virus versus immune response) in the murine model by comparing infected BALB/c pups with infected SCID (immunodeficient) pups. Specific Aim 3 will determine if autoreactive lymphocytes to bile duct antigens are present in the murine model by performing in-vitro T-cell proliferation studies. Specific Aim 4 will characterize the inflammatory immune response in human liver tissue obtained at the time of diagnosis of BA with immunohistochemistry studies. Cytokine profiles will be characterized by cytokine mRNA expression.