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Arnold Han， m.d., Ph.D.的五年综合培训计划，以使其发展成为一名独立的内科科学家。韩博士是一名临床胃肠病学家，拥有免疫学博士学位。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“腹腔疾病的上皮内T细胞反应”的提案中，韩博士旨在更好地了解腹腔疾病（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。该研究进一步研究了乳糜泻患者的上皮内T淋巴细胞（T- iel）在对谷蛋白的反应中被有意招募到肠道。t - iel是导致乳糜泻有害后果的细胞，包括肠道损伤和淋巴瘤的发展。作为后续研究，该建议旨在更好地了解T- iel在乳糜泻中被激活并招募到肠道的机制。该研究探索了一种假设，即谷蛋白特异性CD4+ T细胞反应能够使T- iel反应针对谷蛋白以外的抗原。本研究旨在探讨乳糜泻中T- iel反应的性质和机制：1)通过外周血和组织中T细胞功能的研究，探讨谷蛋白在乳糜泻中激活T细胞的机制。2)研究谷蛋白使CD8+ T细胞损伤CD的机制。3)通过人源化小鼠模型抗原特异性T- iel反应的研究，分析T- iel被激活并募集到肠上皮的机制。这些目标利用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开发预防和治疗乳糜泻和其他自身免疫性疾病的新方法成为可能。同时，韩博士将完成一个结构化的职业发展培训项目，由斯坦福大学医学院胃肠病学和肝脏病学部门的导师和其他教师监督。该计划将包括教学、临床和管理经验，以实现韩博士成为一名成功、独立的内科科学家的最终目标。