The Intraepithelial T cell Response in Celiac Disease

描述（由申请人提供）：本提案概述了候选人Arnold Han，M.D.的五年综合培训计划，哲学博士、作为一个独立的物理学家和科学家。韩医生是一名经过临床培训的胃肠病学家，拥有博士学位。在免疫学上。他在斯坦福大学微生物学和免疫学教授、霍华德休斯医学研究所研究员马克·戴维斯博士的指导下进行博士后研究。在他题为“乳糜泻中的上皮内T细胞反应”的提案中，韩博士旨在更好地了解乳糜泻（CD），这是一种影响数百万美国人以及全球更多人的不可治愈的自身免疫性疾病。该研究进一步调查了CD中的上皮内T淋巴细胞（T-IEL）被故意招募到肠道以响应麸质的观察结果。T-IEL是对CD的有害后果负责的细胞，包括肠损伤和淋巴瘤发展。作为后续行动，该提案旨在更好地了解T-IEL被激活并招募到CD肠道的机制。该研究探讨了这样一种假设，即谷蛋白特异性CD 4 + T细胞应答能够使T-IEL应答针对谷蛋白以外的抗原。拟议的研究通过以下目的调查CD中T-IEL反应的性质和机制：1）通过研究外周血和组织中的T细胞功能，检查麸质在乳糜泻中激活T细胞的机制。2)检查麸质通过CD中的CD 8 + T细胞使组织损伤的机制。3)通过在人源化小鼠模型中研究抗原特异性T-IEL应答，分析T-IEL被激活并募集至肠上皮的机制。这些目标充分利用了韩博士在胃肠病学方面的临床培训，他在人类粘膜T细胞研究方面的博士后研究培训，以及Mark Davis实验室和合作者的专业知识。这些目标的成功完成可能最终使新的方法在预防和治疗CD和其他自身免疫性疾病的发展。同时，韩博士将完成一个结构化的职业发展培训计划，由导师在胃肠病学和肝病学部门和其他教师在斯坦福大学医学院监督。该计划将包括必要的教学，临床和管理经验，以实现韩博士的最终目标，成为一个成功的，独立的医生科学家。

DESCRIPTION (provided by applicant): This proposal outlines an integrative five-year training program for the candidate, Arnold Han, M.D., Ph.D., in his development as an independent physician-scientist. Dr. Han is clinically trained as a gastroenterologist and has a Ph.D. in immunology. He is doing postdoctoral research under the mentorship of Dr. Mark Davis, Professor of Microbiology and Immunology at Stanford University and Investigator with the Howard Hughes Medical Institute. In his proposal entitled "The intraepithelial T cell response in celiac disease", Dr. Han aims to better understand celiac disease (CD), an incurable autoimmune disease that affects millions of Americans, and many more worldwide. The research further investigates the observation that intraepithelial T lymphocytes (T-IEL) in CD are deliberately recruited to the intestine in response to gluten. T-IELs are the cells held responsibl for the detrimental consequences of CD, including intestinal damage and lymphoma development. As a follow up, the proposal aims to better understand mechanisms through with T-IEL are activated and recruited to the intestine in CD. The research explores the hypothesis that gluten-specific CD4+ T cell responses enable T-IEL responses directed against antigens other than gluten. The proposed research investigates the nature and mechanisms of T-IEL responses in CD through the following aims: 1) Examine the mechanisms through which gluten enables �� T cell activation in celiac disease through the study of �� T cell function in peripheral blood and tissue. 2) Examine the mechanisms through which gluten enables tissue damage by CD8+ T cells in CD. 3) Analyze mechanisms through which T-IELs are activated and recruited to the intestinal epithelium through the study of antigen-specific T-IEL responses in humanized mouse models. These aims leverage Dr. Han's clinical training in gastroenterology, his post-doctoral research training in the study of human mucosal T cells, and the expertise of the Mark Davis laboratory and collaborators. Successful completion of these aims may ultimately enable the development of novel approaches in the prevention and treatment of CD and other autoimmune diseases. Concurrently, Dr. Han will complete a structured career development-training program, overseen by mentors within the Division of Gastroenterology and Hepatology and other faculty at the Stanford University School of Medicine. This plan will include didactic, clinical, and managerial experience necessary to achieve Dr. Han's ultimate goal of becoming a successful, independent physician-scientist.