Effect of Ag-specific CD8+ T cell deletion on diabetogenesis in the NOD mouse

描述（由申请人提供）：候选人：研究者，NCSU-CVM兽医肿瘤学家，免疫学博士学位。他的近期目标是继续一项最近开始的项目，研究使用细胞毒性I类四聚体来消除1型糖尿病（T1D）中的致病性CD8+ T细胞。他的长期目标是领导一个外部资助的基础研究实验室，研究T细胞免疫的调节，这将有望导致自身免疫和癌症的创新治疗策略的发展。几年来，该候选人一直在他的赞助人，北卡罗来纳大学- ch免疫学凯南教授Jeffrey Frelinger博士的实验室合作。根据提议的4年奖励，候选人将把他的研究项目从北卡罗来纳大学- ch转移到他将在NCSU的新设施中建立的实验室。为了协助这一过渡，并在研究、学术生产力和职业发展方面提供指导，候选人将有两个共同赞助人：肿瘤学家和前导师Hauck博士（NCSU）；Tisch博士（UNC-CH）是T1D专家，也是候选人当前项目的合作研究员。与导师有计划的非正式会议，以及其他专业培训，将有助于候选人成长为独立的科学家。环境：主办者在科学生产力、资金和临床科学家培训方面有着令人印象深刻的记录。这两个机构的实验室和核心设施资源都非常适合完成拟议的工作，而且学术氛围也很好。候选人所在的部门致力于他作为一名科学家的职业发展，并支持研究所需的时间要求。研究项目：在T1D NOD模型中研究CD8+ T细胞与糖尿病发生的关系，并发现了一种识别IGRP206-214的显性胰岛浸润克隆型。我们的初步数据表明，这些T细胞可以通过细胞毒性高亲本四聚体在体内选择性地删除；然而，如果致病性T细胞重新扩张以填补由缺失产生的克隆型“空间”，这种耐受性策略可能最终失败。我们建议评估在这个空缺中优先扩增非致病性T细胞的策略，如果成功，研究这种双重策略对胰岛T细胞群功能组成的影响。相关性：这项研究将有助于确定杀手T细胞在青少年糖尿病中的作用，并有可能确定治疗这种疾病的新策略。

DESCRIPTION (provided by applicant): Candidate: The investigator is a veterinary oncologist at NCSU-CVM, with a PhD in immunology. His immediate goals are to continue a recently-begun project examining the use of cytotoxic class I tetramers to eliminate pathogenic CD8+ T cells in type 1 diabetes (T1D). His long-term goals are to direct an externally-funded, basic research laboratory investigating the regulation of T cell immunity, which will hopefully lead to the development of innovative therapeutic strategies for autoimmunity and cancer. For several years the candidate has worked collaboratively in the laboratory of his sponsor, Dr. Jeffrey Frelinger, Kenan Professor of Immunology at UNC-CH. Under the proposed 4-year award, the candidate will transition his research project from UNC-CH into a laboratory that he will establish in a new facility at NCSU. To assist in this transition, and to provide guidance on research, scholarly productivity, and career development, the candidate will have two co-sponsors: Dr. Hauck (NCSU), an oncologist and former mentor; and Dr. Tisch (UNC-CH), an expert on T1D and a co-investigator on the candidate's current project. Planned and informal meetings with mentors, as well as other specialized training, will assist in the candidate's growth as an independent scientist. Environment: The sponsor has an impressive track record of scientific productivity, funding, and training^ clinician-scientists. The laboratory and core facility resources at both institutions are well-suited to completing the proposed work, and the intellectual climate is excellent. The candidate's department is committed to his career development as a scientist and supports the time requirements necessary for research. Research project: Studies in the NOD model of T1D implicate CD8+ T cells in diabetogenesis, and a dominant islet-infiltrating clonotype that recognizes IGRP206-214 has been identified. Our preliminary data show that these T cells can be selectively deleted in vivo by a cytotoxic high-avidity cognate tetramer; however, this tolerogenic strategy may ultimately fail if pathogenic T cells re-expand to fill the clonotype "space" created by deletion. We propose to evaluate strategies for preferentially expanding non-pathogenic T cells within this vacancy, and if successful, investigate the effects of this dual strategy on the functional composition of islet T cell populations. Relevance: This research will help to determine the role of killer T cells in juvenile diabetes, and potentially characterize a new strategy for treating this disease.