The Intraepithelial T cell Response in Celiac Disease

乳糜泻中的上皮内 T 细胞反应

• 批准号: 9085282
• 负责人: Arnold Han
• 金额: $ 1.34万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9085282
• 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; Health; 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; humanized mouse; insight; intestinal epithelium; intraepithelial; medical schools; mouse model; novel; novel diagnostics; novel strategies; novel therapeutics; peripheral blood; professor; 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（由适用提供）：该提案概述了为候选人Arnold Han，M.D。，Ph.D。的综合培训计划，以作为独立的物理科学家的发展。 Han博士在临床上接受了胃肠病医生的培训，并拥有博士学位。在免疫学上。他是在斯坦福大学微生物学和免疫学教授马克·戴维斯（Mark Davis）和霍华德·休斯医学院（Howard Hughes Medical Institute）的调查员马克·戴维斯（Mark Davis）的心态下进行博士后研究。 Han博士在其题为“乳糜泻的上皮内T细胞反应”的提议中，旨在更好地了解腹腔疾病（CD），腹腔疾病（CD）是一种无法治愈的自身免疫性疾病，影响了数百万美国人，并且在全球范围内影响更多。该研究进一步研究了以下观察结果：CD中的上皮内T淋巴细胞（T-EIL）被故意招募到肠道中，以响应面筋。 T-iels是负责CD的有害后果的细胞，包括肠道损伤和淋巴瘤发育。随后，该提案旨在通过T-EIL通过T-EIL更好地理解机制，并将其招募到CD中的肠。该研究探讨了以下假设：麸质特异性CD4+ T细胞反应可实现针对麸质以外的抗原的T-EIL反应。拟议的研究通过以下目的调查了CD中T-EIL反应的性质和机制：1）检查麸质通过研究外周血和组织中T细胞功能在腹腔疾病中激活的机制。 2）检查麸质在CD中造成CD8+ T细胞的组织损伤的机制。 3）分析通过研究人源化小鼠模型中抗原特异性T-EL的反应的研究，通过研究抗原特异性T-EL响应将T-iels激活并募集到肠上皮的机制。这些目的利用了汉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马克·戴维斯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可以发展用于预防和治疗CD和其他自身免疫性疾病的新方法。同时，Han博士将完成一项结构化的职业发展培训计划，并由斯坦福大学医学院的胃肠病学和肝病学和其他教职员工负责监督。该计划将包括实现Han博士成为成功，独立的身体科学家的最终目标所必需的教学，临床和管理经验。