The Intraepithelial T cell Response in Celiac Disease

乳糜泻中的上皮内 T 细胞反应

• 批准号: 9407276
• 负责人: Arnold Han
• 金额: $ 13.05万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2020-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9407276
• 关键词: Intraepithelial; cell; Response; Celiac; Disease

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.

描述（由申请人提供）：本提案概述了候选人阿诺德·汉（Arnold Han，医学博士、哲学博士）作为一名独立医师科学家的发展的综合五年培训计划。韩医生接受过胃肠病学临床培训，并拥有博士学位。在免疫学中。他正在斯坦福大学微生物学和免疫学教授兼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。在题为“乳糜泻中的上皮内 T 细胞反应”的提案中，Han 博士旨在更好地了解乳糜泻 (CD)，这是一种无法治愈的自身免疫性疾病，影响着数百万美国人以及全世界更多的人。该研究进一步调查了 CD 中的上皮内 T 淋巴细胞 (T-IEL) 因麸质反应而被故意招募到肠道的观察结果。 T-IEL 是对 CD 的有害后果负责的细胞，包括肠道损伤和淋巴瘤发展。作为后续行动，该提案旨在更好地了解 CD 中 T-IEL 被激活并招募到肠道的机制。该研究探讨了这样的假设：麸质特异性 CD4+ T 细胞反应能够使 T-IEL 反应针对麸质以外的抗原。拟议的研究通过以下目标研究 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) 检查麸质导致 CD 中 CD8+ T 细胞损伤组织的机制。 3) 通过研究人源化小鼠模型中抗原特异性 T-IEL 反应，分析 T-IEL 被激活并招募到肠上皮的机制。这些目标利用了 Han 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。成功完成这些目标可能最终能够开发出预防和治疗克罗恩病和其他自身免疫性疾病的新方法。与此同时，韩博士将完成一项结构化的职业发展培训计划，该计划由斯坦福大学医学院胃肠病学和肝病学部门的导师以及其他教员监督。该计划将包括实现韩博士成为一名成功的独立医师科学家的最终目标所需的教学、临床和管理经验。