SMOOTH MUSCLE APOPTOSIS

描述(申请人提供)：与坏死不同，细胞凋亡是典型的 被认为是“无声的”，即自给自足且不具煽动性。我们有 建立了一种调控血管内皮细胞(SMC)凋亡的系统 在活体大鼠颈动脉，并使用该系统测定SMC FADD过度表达或Fas连接启动的细胞凋亡包括 促炎基因表达的特定程序，导致 巨噬细胞的募集。在本申请中，我们建议进一步定义 这个基因表达的程序，决定了它是通过什么机制 调控，并进一步研究平滑肌细胞的后果 体内的细胞凋亡。为此，我们提出了以下具体目标： 特异性目的1：利用tet调控FADD在大鼠颈动脉中的表达 为了确定新生内膜中SMC凋亡的长期后果， 包括临床上重要的血管重建过程， 血栓形成和斑块破裂。 特异性目的2.确定基因表达程序是否被激活 人类SMC中的Fas包括额外的基因，无论它是细胞类型特异性的， 以及组分基因表达的激活如何反映出 特定的信号转导途径。 特异性目的3.确定Fas通过的信号转导途径(S 激活导致人血管内皮细胞转录上调。 特异靶向4.确定SMC对 Fas诱导的细胞凋亡，可能在某些情况下促进SMC的增殖 情况。

DESCRIPTION (provided by applicant): Unlike necrosis, apoptosis is classically considered to be "silent," i.e., self-contained and non-inflammatory. We have developed a system for regulating apoptosis of smooth muscle cells (SMCs) in the rat carotid artery in vivo, and have used this system to determine that SMC apoptosis initiated by FADD over expression, or by Fas ligation, includes a specific program of expression of pro-inflammatory genes that results in recruitment of macrophages. In this application, we propose to further define this program of gene expression, determine the mechanism through which it is regulated, and further investigate the consequences of smooth muscle cell apoptosis in vivo. To do this, we propose the following specific aims: SPECIFIC AIM 1: Use tet-regulated expression of FADD in the rat carotid artery to determine the long-term consequences of SMC apoptosis in the neointima, including the clinically important processes of vascular remodeling, thrombosis, and plaque rupture. SPECIFIC AIM 2. Determine whether the program of gene expression activated by Fas in human SMCs includes additional genes, whether it is cell-type specific, and how activation of expression of component genes reflect activation of specific signal transduction pathways. SPECIFIC AIM 3. Determine the signal transduction pathway(s) through which Fas activation leads to transcript up regulation in human SMCs. SPECIFiC AIM 4. Determine the mechanisms that regulate SMC resistance to Fas-induced apoptosis and that may promote SMC proliferation under some circumstances.