Immunologic Mechanism/Destruction/Biliary Artesia

描述(由申请人提供) 我的职业目标是成为一名内科科学家，照顾患有 肝脏疾病，并在研究领域做出了重大贡献 儿科肝病。我对胆道闭锁(BA)及其 自我接触这种疾病以来可能的致病机制 儿科住院医生。在过去的一年里，我一直在大学学习免疫学。 斯蒂芬·米勒博士实验室，西北大学博士。我计划这样做 长期留在学术界，作为一名有目标的研究科学家 明确界定免疫系统在糖尿病发病机制中的作用 胆道闭锁和其他儿科肝病。 胆道闭锁是一种进行性的婴儿期炎症性胆管病 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，发病机制 BA涉及病毒诱导的、递增的自身反应性CD4+Th1细胞介导的 胆管破坏。A组轮状病毒小鼠模型将用于 验证这一假设，并导致病毒诱导的进行性炎症 破坏肝外和肝内胆管导致肝外胆管 导管纤维化和闭塞。关于人肝组织的有限研究 在诊断BA时获得的也将进行检查。具体目标1 将表征这种小鼠模型中的炎性免疫反应 通过使用免疫组织化学和流式细胞术进行研究。 还将进行细胞因子图谱的表征。具体目标2 将决定导管破坏的主要媒介(病毒与 通过比较感染的BALB/c幼鼠和 受感染的SCID(免疫缺陷)幼崽。具体目标3将决定是否 小鼠模型中存在对胆管抗原有自身反应的淋巴细胞 通过进行体外T细胞增殖研究。具体目标4将 表征人肝组织的炎性免疫反应 免疫组织化学检测诊断BA的时间。细胞因子 将通过细胞因子mRNA的表达来表征图谱。

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.