The Intraepithelial T cell Response in Celiac Disease

乳糜泻中的上皮内 T 细胞反应

• 批准号: 8821937
• 负责人: Arnold Han
• 金额: $ 14.4万
• 依托单位: STANFORD UNIVERSITY
• 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/8821937
• 关键词: Affect; Alleles; American; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; Automobile Driving; B-Lymphocytes; Barley; Benign; CD4 Positive T Lymphocytes; CD8B1 gene; Celiac Disease; Cell physiology; Cells; Clinical; Data; Development; Diabetes Mellitus; Dietary Proteins; Disease; Doctor of Medicine; Doctor of Philosophy; Faculty; Gastroenterologist; Gastroenterology; Gluten; Goals; HLA-DQ8 antigen; Hepatology; Human; Immune; Immunology; Inbred NOD Mice; Individual; Ingestion; Injury; Institutes; Insulin-Dependent Diabetes Mellitus; Interleukin-15; Intestines; Intraepithelial T-Lymphocyte; Laboratories; Lead; Licensing; Life; Lymphocyte antigen; Lymphoma; Lymphomagenesis; MHC Class II Genes; Malabsorption Syndromes; Mediating; Medical; Mentors; Mentorship; Microbiology; Modeling; Morbidity - disease rate; Multiple Sclerosis; Nature; Non obese; Nutrient; Phase; Physicians; Postdoctoral Fellow; Prevention; Process; Proteins; Quality of life; Recruitment Activity; Research; Research Personnel; Research Training; Rheumatoid Arthritis; Scientist; Small Intestines; Structure; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Tissues; Training; Training Programs; Transgenic Mice; Universities; Virus; Western World; Wheat; career development; diabetic; experience; follow-up; genetic association; insight; intestinal epithelium; intraepithelial; medical schools; mouse model; novel; novel diagnostics; novel strategies; peripheral blood; professor; public health relevance; response

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·韩（Arnold Han）医学博士、博士的综合五年培训计划，以帮助他成为一名独立的医师兼科学家。韩博士接受过胃肠病学家的临床培训。他拥有免疫学博士学位，目前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。 Han 博士在题为“乳糜泻中的上皮内 T 细胞反应”的提案中，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世界更多人的无法治愈的自身免疫性疾病。 CD 中的上皮内 T 淋巴细胞 (T-IEL) 因麸质而被故意招募到肠道，T-IEL 是 CD 的缺点的细胞，包括肠道损伤和肠道损伤。作为后续研究，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，该研究探讨了麸质特异性 CD4+ T 细胞反应使 T-IEL 反应能够针对 CD 的假设。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 �� T 细胞，检查麸质在乳糜泻中激活 �� T 细胞的机制。功能2) 检查 CD8+ T 细胞中麸质导致组织损伤的机制。 3) 通过研究抗原特异性 T- 来分析 T-IEL 被激活并募集到肠上皮的机制。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。同时，韩博士将在胃肠病学和肝病学部门的导师的监督下完成一个结构化的职业发展培训计划。该计划将包括韩博士成为一名成功的独立医师科学家的最终目标所必需的教学、临床和管理经验。