Role of caspase 7 in T cell function

Caspase 7 在 T 细胞功能中的作用

基本信息

批准号：
6891438
负责人：
SAQUIB A LAKHANI
金额：
$ 13.03万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-09 至 2008-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this project is to understand the mechanisms underlying the development and termination of the CD4 T cell arm of the immune response. These are fundamental processes with potentially wide health-related implications, from comprehending the normal immune response to grasping the possible consequences of a failure to eliminate activated T cells, such as autoimmune disease. Naive T cells undergo clonal expansion and differentiation in response to antigen, then exert their effects primarily through the secretion of cytokines. Subsequently, it is necessary to restore homeostasis by deleting this large population of activated cells by apoptosis. Caspase 7, a member of a family of proteases known to be important for cell death, is activated in apoptotic cells, though little is known of its function. Surprising preliminary data shows that not only are caspase 7 knockout T cells partially resistant to apoptosis, but they also fail to secrete interferon gamma, an important effector cytokine, and produce reduced amounts of IL-2, a cytokine important for both T cell proliferation and apoptosis. The candidate proposes to further study the role of caspase 7 in T cell cytokine secretion and apoptosis. In vitro studies of proliferation and cytokine production in caspase 7 deficient T cells, and in vivo immunologic challenge, will further test the hypothesis that caspase 7 is important for T cell function. A mechanistic link between caspase 7 and cytokine secretion will be sought by determining its effects on signaling pathways that influence cytokine production and by identifying its substrates with two approaches: mass spectrometry of differences in protein cleavage between wild type and knockout T cells; and yeast two-hybrid screening. The role of caspase 7 in T cell apoptosis will be approached by determining the effects of its combined deficiency with caspase 3, a highly related protease that is important, but not necessary, for apoptosis. The applicant is completing a fellowship at Yale University in Pediatric Critical Care, and will continue there as a junior faculty member. The proposed research will be done in the Department of Immunobiology, an ideal location for research training due to quality faculty, strong mentorship, breadth of research topics and outstanding facilities. This K08 award will greatly assist his research into apoptosis and T cell immunology, and provide him with time and resources to develop into an independent basic science investigator.

描述（由申请人提供）：该项目的长期目标是了解免疫反应的 CD4 T 细胞臂发生和终止的潜在机制。这些是具有潜在广泛健康相关影响的基本过程，从理解正常的免疫反应到掌握未能消除激活的 T 细胞（例如自身免疫性疾病）的可能后果。初始 T 细胞响应抗原进行克隆扩增和分化，然后主要通过分泌细胞因子发挥作用。随后，有必要通过细胞凋亡删除大量活化细胞来恢复体内平衡。 Caspase 7 是已知对细胞死亡很重要的蛋白酶家族的成员，它在凋亡细胞中被激活，但对其功能知之甚少。令人惊讶的初步数据表明，caspase 7 敲除的 T 细胞不仅部分抵抗细胞凋亡，而且它们也无法分泌干扰素 γ（一种重要的效应细胞因子），并且产生减少量的 IL-2（一种对 T 细胞增殖和免疫功能都很重要的细胞因子）。细胞凋亡。候选人提出进一步研究caspase 7在T细胞细胞因子分泌和凋亡中的作用。对 caspase 7 缺陷 T 细胞增殖和细胞因子产生的体外研究以及体内免疫挑战将进一步检验 caspase 7 对 T 细胞功能重要的假设。 Caspase 7 和细胞因子分泌之间的机制联系将通过确定其对影响细胞因子产生的信号通路的影响以及通过两种方法鉴定其底物来寻找：质谱分析野生型和敲除 T 细胞之间蛋白质裂解的差异；和酵母二杂交筛选。 Caspase 7 在 T 细胞凋亡中的作用将通过确定其与 Caspase 3 的联合缺陷的影响来探讨，Caspase 3 是一种高度相关的蛋白酶，对细胞凋亡很重要，但不是必需的。申请人即将完成耶鲁大学儿科重症护理的奖学金，并将继续担任初级教员。拟议的研究将在免疫生物学系进行，该系拥有高素质的师资力量、强有力的指导、广泛的研究课题和出色的设施，是研究培训的理想场所。此次K08奖将极大地帮助他在细胞凋亡和T细胞免疫学方面的研究，并为他提供时间和资源，以发展成为一名独立的基础科学研究者。