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The quantitative biology of CTLA4 splice variants in T1D

T1D 中 CTLA4 剪接变体的定量生物学

基本信息

批准号：
7798450
负责人：
Zhibin Chen
金额：
$ 228.92万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-20 至 2014-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Insulin-dependent diabetes mellitus (IDDM), or type 1 diabetes (T1D), is caused by T-cell mediated, spontaneous autoimmune destruction of the insulin-producing 2 cells in pancreatic islets. A number of genetic factors contribute to T1D risks. The CTLA4 locus has been implicated in risk for T1D by many genetic studies. There is no report of complete loss of function of CTLA4 in humans. It is not the "all or nothing" CTLA4 signaling, but the subtle quantitative variations of expression associated with genetic polymorphisms, that are attributed to susceptibility to T1D. A number of T1D-risk polymorphisms in the CTLA4 locus have been associated with reduced expression of CTLA4 or its splice variants. However, it remains unclear whether and how CTLA4 splice variants function in etiopathogenesis of T1D and how quantitative reduction of a particular splice variant(s) contributes to the etiological and pathogenic pathways of T1D. To validate the impact of CTLA4 splice variant reduction on susceptibility to T1D, RNAi knockdown mouse models will be established, following a proof-of-principle study. This proposal aims to establish the causative role of CTLA4 splice variant reduction in T1D development, and to uncover novel mechanisms of the quantitative biology of CTLA4 splice variants in T1D pathogenesis. Specifically, 1) novel RNAi transgenic mouse models targeting specific CTLA4 splice variants will be generated to pinpoint the impact of a particular splice variant(s) in T1D pathogenesis; 2) In vitro human studies will be used to define the quantitative impact of CTLA4 splice variants on T cells responses and regulations. New technologies will be applied to uncover novel mechanisms by which the quantitative variations of CTLA4 splice variants alter T1D risk. This knowledge will help identify new strategies to bridge a diversity of immune tolerance mechanisms to protect beta cells. PUBLIC HEALTH RELEVANCE: Type 1 diabetes causes significant morbidity and premature mortality. Variations of the CTLA4 gene are associated with a higher risk of developing this disease. An understanding of the functional impact of CTLA4 genetic variations will help find new therapeutic targets for type 1 diabetes.

描述（由申请人提供）：胰岛素依赖型糖尿病（IDDM）或1型糖尿病（T1 D）是由T细胞介导的胰岛中产生胰岛素的2细胞的自发性自身免疫破坏引起的。许多遗传因素导致T1 D风险。CTLA 4基因座已被许多遗传学研究表明与T1 D的风险有关。没有关于人类CTLA 4功能完全丧失的报道。这不是“全有或全无”的CTLA 4信号，而是与遗传多态性相关的表达的细微定量变化，这归因于T1 D的易感性。CTLA 4基因座中的许多T1 D风险多态性与CTLA 4或其剪接变体的表达降低相关。然而，CTLA 4剪接变体是否以及如何在T1 D的发病机制中起作用以及特定剪接变体的定量减少如何有助于T1 D的病因学和致病途径仍不清楚。为了验证CTLA 4剪接变体减少对T1 D易感性的影响，将在原理验证研究后建立RNAi敲除小鼠模型。该提案旨在确定CTLA 4剪接变体减少在T1 D发展中的致病作用，并揭示CTLA 4剪接变体在T1 D发病机制中的定量生物学新机制。具体而言，1）将产生靶向特定CTLA 4剪接变体的新型RNAi转基因小鼠模型，以查明特定剪接变体在TlD发病机制中的影响; 2）将使用体外人体研究来定义CTLA 4剪接变体对T细胞应答和调节的定量影响。新技术将用于揭示CTLA 4剪接变异体的定量变化改变T1 D风险的新机制。这些知识将有助于确定新的策略，以弥合多种免疫耐受机制，以保护β细胞。公共卫生关系： 1型糖尿病导致显著的发病率和过早死亡率。CTLA 4基因的变异与患这种疾病的风险较高有关。了解CTLA 4基因变异的功能影响将有助于找到1型糖尿病的新治疗靶点。