Gene Therapy for Long-Term Myocardial Protection

描述（由申请方提供）：调节性细胞凋亡对胸腺中的T细胞发育至关重要，并控制外周中的T细胞依赖性适应性免疫。2-连环蛋白，T细胞因子1（TCF-1）的共激活物，和类维生素A相关孤儿受体γ t（ROR 3 t）都通过上调抗凋亡Bcl-xL来调节胸腺细胞存活。在研究ROR 3 t的过程中，我们已经确定2- catenin/TCF-1作为控制ROR 3 t介导的胸腺细胞存活的潜在上游通路。TCF-1的缺失导致胸腺细胞凋亡和下调ROR 3 t，而稳定的2-catenin（2-catTg）的转基因表达，它激活TCF-1组成，导致胸腺细胞的存活增强和上调ROR 3 t。与其在胸腺细胞中的存活作用相反，2-catTg上调促凋亡Bid和表面Fas，并通过促进活化诱导的细胞死亡（AICD）增强超抗原葡萄球菌肠毒素B（SE B）诱导的外周T细胞缺失。因此，我们假设2-连环蛋白/TCF途径在发育中的T细胞和外周成熟T细胞的凋亡调节中利用不同的机制。在本研究的前两个目的中，我们建议阐明2-catenin/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，我们将确定我们是否可以通过操纵2-连环蛋白调节的T细胞存活来控制T细胞依赖性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.