Gene Therapy for Long-Term Myocardial Protection

描述(申请人提供)：调节的细胞凋亡是胸腺T细胞发育的关键，并控制外周T细胞依赖的获得性免疫。T细胞因子1(TCF-1)的共激活因子2-连环蛋白(2-catenin)和维甲酸相关的孤儿受体γt(ROR3t)均通过上调抗凋亡的Bclxl来调节胸腺细胞的存活。在研究ROR3t的过程中，我们发现2-catenin/TCF-1是控制ROR3t介导的胸腺细胞存活的一个潜在的上游途径。TCF-1的缺失导致胸腺细胞的凋亡和ROR3t的下调，而稳定的2-连环蛋白(2-catenin，2-catenin)的转基因表达可以促进胸腺细胞的存活，上调ROR3t的表达。与其在胸腺细胞中的存活作用相反，2-catTg通过促进活化诱导的细胞死亡(AICD)上调促凋亡的BID和表面Fas，并增强超抗原葡萄球菌肠毒素B(SEB)诱导的外周T细胞的缺失。因此，我们假设2-连环蛋白/TCF通路在调节发育中的T细胞和外周成熟T细胞中的凋亡方面使用了不同的机制。在这项研究的前两个目标中，我们建议阐明2-连环蛋白/TCF-1调节胸腺细胞和外周T细胞凋亡的机制。在最后一个目标中，我们将确定是否可以通过操纵2-连环蛋白调节的T细胞存活来控制T细胞依赖的同种异体移植排斥反应。

DESCRIPTION (provided by applicant): Regulated apoptosis is critical to T cell development in the thymus and controls T cell- dependent adaptive immunity in periphery. 2-catenin, a coactivator of T cell factor 1 (TCF-1), and retinoid-related orphan receptor gamma t (ROR3t) both regulate thymocyte survival via the up-regulation of anti-apoptotic Bcl-xL. In the process of studying ROR3t, we have identified 2- catenin/TCF-1 as a potential upstream pathway that controls ROR3t-mediated thymocyte survival. Deletion of TCF-1 resulted in thymocyte apoptosis and down-regulated ROR3t, whereas transgenic expression of a stabilized 2-catenin (2-catTg), which activated TCF-1 constitutively, led to enhanced thymocyte survival and up-regulated ROR3t. In contrast to its survival role in thymocytes, 2-catTg up-regulated pro-apoptotic Bid and surface Fas, and enhanced super-antigen staphylococcal enterotoxin B (SEB)-induced deletion of peripheral T cells by promoting activation-induced cell death (AICD). We thus hypothesize that the 2- catenin/TCF pathway utilizes distinct mechanisms in the regulation of apoptosis in developing T cells and peripheral mature T cells. In the first two aims of this study, we propose to elucidate the mechanisms responsible for 2-catenin/TCF-1-regulated apoptosis in thymocytes and peripheral T cells. In the last aim, we will determine whether we can control T cell-dependent allograft rejection by manipulating 2-catenin-regulated T cell survival.