Mechanism of apoptosis in lung vascular smooth muscle

描述(由申请人提供)： 原发性肺动脉高压(PPH)是罕见的，但通常是致命的，在食欲抑制药的使用者中发病率增加。它的特点是肺血管阻力增加，因为肺动脉壁增厚。然而，调控平滑肌细胞数量的细胞机制还没有明确。缺乏这样的知识干扰了旨在预防和/或治疗这种疾病的新治疗策略的发展。我的长期目标是确定人肺动脉平滑肌细胞(HPASMC)凋亡的调控机制。本应用的目的是具体评估GATA转录因子的作用。该应用的中心假设是GATA因子调节细胞凋亡和存活。这一假说是建立在强大的初步数据的基础上的，这些数据表明：1)GATA-4和-6在HPASMC中表达，2)凋亡刺激下调GATA活性，3)5-羟色胺和内皮素-1发挥抗凋亡信号并增强GATA活性。这项拟议研究的基本原理是，一旦了解了调节肺血管中层增厚的机制，它将导致可用于预防和/或治疗PPH的新策略，从而降低与这种疾病相关的发病率和死亡率。我特别准备承担这项拟议的研究，因为我的实验室一直在研究GATA因素，而且许多技术和试剂已经可用。中心假说将得到验证，应用的目标将通过追求两个特定的目标来实现：1)确定一氧化氮和维甲酸诱导HPASMC凋亡的机制；2)确定5-羟色胺和内皮素-1发挥抗凋亡信号的机制。这项拟议的工作具有创新性，因为它将使用一种已用于心肌研究的方法来研究肺中的新转录因子。我期望GATA因子参与HPASMC的凋亡调控。这些结果将具有重要意义，因为它们有望为产后出血的预防和治疗干预提供新的制剂。此外，预计这一结果将从根本上推进肺细胞生物学领域的发展。

DESCRIPTION (provided by applicant): Primary pulmonary hypertension (PPH) is rare, but often fatal, with increased incidence in users of appetite suppressants. It is characterized by increased lung vascular resistance due to thickening of pulmonary arterial walls. The cellular mechanisms that regulate smooth muscle cell number, however, have not been defined. Lack of such knowledge interferes with the development of new therapeutic strategies that are designed to prevent and/or treat this condition. My long-range goal is to identify the mechanisms for the regulation of apoptosis in human pulmonary artery smooth muscle cells (HPASMC). The objective of this application is to evaluate specifically the role of GATA transcription factors. The central hypothesis of the application is that GATA factors regulate apoptosis and survival. The hypothesis has been formulated on the basis of strong preliminary data, which suggest that i) GATA-4 and -6 are expressed in HPASMC, ii) apoptotic stimuli downregulate the GATA activity, and iii) serotonin and endothelin-1 exert anti-apoptotic signaling and enhance the GATA activity. The rationale for the proposed research is that, once knowledge of the mechanisms that regulate the lung vascular medial thickening has been obtained, it will lead to new strategies that can be used to prevent and/or treat PPH, thereby reducing the morbidity and mortality that are associated with this condition. I am uniquely prepared to undertake the proposed research because my lab has been studying GATA factors, and many of the techniques and reagents are already available. The central hypothesis will be tested and the objective of the application accomplished by pursuing two specific aims: 1) Identify the mechanisms of HPASMC apoptosis induced by nitric oxide and retinoic acid, and 2) Determine the mechanisms by which serotonin and endothelin-1 exert anti-apoptotic signaling. The proposed work is innovative, because it will investigate novel transcription factors in lung using an approach that has been used in the studies of cardiac muscle. It is my expectation that GATA factors are involved in the regulation of apoptosis of HPASMC. These results will be significant because they are expected to provide new agents for preventative and therapeutic interventions of PPH. In addition, it is expected that the results will fundamentally advance the field of lung cell biology.