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，但往往是致命的，与食欲抑制剂的使用者的发病率增加。其特征在于由于肺动脉壁增厚而导致肺血管阻力增加。然而，调节平滑肌细胞数量的细胞机制尚未确定。缺乏这种知识会干扰旨在预防和/或治疗这种疾病的新治疗策略的开发。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。本申请的目的是专门评估加塔转录因子的作用。本申请的中心假设是加塔因子调节细胞凋亡和存活。该假设是基于强有力的初步数据制定的，这些数据表明i）加塔-4和-6在HPASMC中表达，ii）凋亡刺激下调加塔活性，和iii）5-羟色胺和内皮素-1发挥抗凋亡信号传导并增强加塔活性。拟议研究的基本原理是，一旦获得了调节肺血管中膜增厚的机制的知识，它将导致可用于预防和/或治疗PPH的新策略，从而降低与这种情况相关的发病率和死亡率。我已经做好了进行这项研究的准备，因为我的实验室一直在研究加塔因子，而且许多技术和试剂已经可用。将检验中心假设，并通过追求两个具体目标来实现本申请的目的：1）鉴定由一氧化氮和视黄酸诱导的HPASMC凋亡的机制，和2）确定5-羟色胺和内皮素-1发挥抗凋亡信号传导的机制。这项工作是创新的，因为它将使用心肌研究中使用的方法来研究肺中的新型转录因子。因此，我们推测加塔因子可能参与了HPASMC凋亡的调控。这些结果将是显着的，因为他们有望提供新的代理PPH的预防和治疗干预。此外，预计这些结果将从根本上推动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.