Mechanism of apoptosis in lung vascular smooth muscle

肺动脉高压的特征是肺血管阻力增加，部分原因是 肺动脉壁增厚。血管厚度受平滑肌细胞（SMC）的影响 增殖和凋亡。然而，调节肺血管SMC凋亡的机制， 没有被定义。缺乏这方面的知识会妨碍制定新的战略， 和/或治疗肺动脉高压。我的长期目标是确定细胞凋亡的机制， 调节肺血管SMC，以开发基于肺动脉高压的治疗策略， 厚本竞争性续约申请的目的是专门评估 主要抗凋亡蛋白Bcl-xL的基因转录。核心假设是加塔-4调节 Bcl-xL基因转录。这一假设是根据初步数据提出的， 提示i）bcl-x基因启动子调控抗凋亡亚型基因转录区域 Bcl-xL在肺动脉SMC中具有活性，ii）该区域含有加塔-4的结合位点，GATA-4是肺动脉平滑肌细胞的一种特异性受体。 肺特异性SMC调节剂，和iii）肺动脉高压的调节剂改变加塔-4活性，Bcl-2， xL表达和凋亡。这项研究的基本原理是，一旦了解了 肺血管平滑肌细胞凋亡的调控机制，这将导致新的策略，可以 用于治疗肺动脉高压。我准备进行这项研究，因为 研究细胞凋亡和基因调控的技术和试剂在我的实验室是可用的。的 申请的目的将通过追求三个具体目标来实现：1）表征 正常和重塑肺动脉平滑肌中Bcl-xL基因基础转录的调控 2）确定诱导Bcl-xL基因转录的机制，以及3）定义机制 Bcl-xL在正常肺动脉和重塑肺动脉中表达下调的作用。的 拟议的工作是创新的，因为它将调查新的凋亡机制，使用独特的 基于腺病毒的报告系统。我预期加塔-4调节Bcl-xL表达， 控制细胞凋亡。这些结果将是重大的，因为它们有望提供新的代理人 对抗肺动脉高压此外，这些结果将从根本上推进肺生物学领域。

Pulmonary hypertension is characterized by increased pulmonary vascular resistance, in part, due to thickening of pulmonary arterial walls. Vascular thickness is influenced by smooth muscle cell (SMC) proliferation and apoptosis. Mechanisms that regulate pulmonary vascular SMC apoptosis, however, have not been defined. Lack of such knowledge interferes with the development of new strategies to prevent and/or treat pulmonary hypertension. My long-range goal is to identify the mechanisms of apoptotic regulation in pulmonary vascular SMC to develop apoptosis-based therapeutic strategies to reduce vascular thickness. The objective of this competitive renewal application is to evaluate specifically the mechanism of gene transcription of a major anti-apoptotic protein Bcl-xL. The central hypothesis is that GATA-4 regulates Bcl-xL gene transcription. The hypothesis has been formulated on the basis of preliminary data, which suggest that i) the region of bcl-x gene promoter which regulates gene transcription of anti-apoptotic isoform Bcl-xL is active in pulmonary artery SMC, ii) this region contains binding sites for GATA-4 which is a pulmonary-specific SMC regulator, and iii)regulators of pulmonary hypertension alters GATA-4 activity, Bcl- xL expression, and apoptosis. The rationale for the proposed research is that, once knowledge of the regulation of pulmonary vascular SMC apoptosis has been obtained, it will lead to new strategies that can be used to treat pulmonary hypertension. I am uniquely prepared to undertake the proposed research because techniques and reagents to study apoptosis and gene regulation are available in my laboratory. The objective of the application will be accomplished by pursuing three specific aims: 1) Characterize the regulation of basal Bcl-xL gene transcription in smooth muscle from normal and remodeled pulmonary arteries, 2) Identify mechanisms for the induction of Bcl-xL gene transcription, and 3) Define the mechanisms and functions of downregulation of Bcl-xL expression in normal and remodeled pulmonary arteries. The proposed work is innovative because it will investigate novel apoptotic mechanisms using a unique adenovirus-based reporter system. It is my expectation that GATA-4 regulates Bcl-xL expression and controls apoptosis. These results will be significant because they are expected to provide new agents against pulmonary hypertension. In addition, the results will fundamentally advance the field of lung biology.