The quantitative biology of CTLA4 splice variants in T1D

描述(申请人提供)：胰岛素依赖型糖尿病(IDDM)，或1型糖尿病(T1D)，是由T细胞介导的，自发的自身免疫破坏胰岛中产生胰岛素的2细胞引起的。许多遗传因素导致了T1D风险。许多遗传学研究表明，CTLA4基因座与T1D的发病风险有关。目前尚无人类CTLA4功能完全丧失的报道。这不是“全有或全无”的CTLA4信号，而是与遗传多态相关的表达的微妙数量变化，被归因于对T1D的易感性。CTLA4基因座上的许多T1D风险多态与CTLA4或其剪接变异体表达降低有关。然而，目前尚不清楚CTLA4剪接变异体是否以及如何在T1D的发病机制中发挥作用，以及特定剪接变异体(S)的定量减少如何在T1D的病因和致病途径中起作用。为了验证CTLA4剪接变异体减少对T1D易感性的影响，将建立RNAi敲除小鼠模型，并进行原理验证研究。本研究旨在确定CTLA4剪接变异体减少在T1D发生中的作用，并揭示CTLA4剪接变异体在T1D发病机制中的定量生物学新机制。具体地说，1)将建立针对特定CTLA4剪接变体的新型RNAi转基因小鼠模型，以确定特定剪接变体(S)在T1D发病机制中的影响；2)将利用体外人体研究来确定CTLA4剪接变体对T细胞反应和调节的定量影响。新技术将被应用于揭示CTLA4剪接变异体的数量变化改变T1D风险的新机制。这一知识将有助于确定新的策略，以连接多种免疫耐受机制，以保护贝塔细胞。 公共卫生相关性： 1型糖尿病会导致严重的发病率和过早死亡。CTLA4基因的变异与患这种疾病的风险更高相关。了解CTLA4基因变异对功能的影响将有助于寻找1型糖尿病的新治疗靶点。

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.