Prostacyclin synthase and prostacyclin receptor in PH

PH 中的前列环素合酶和前列环素受体

• 批准号: 6642930
• 负责人: MARK W GERACI
• 金额: $ 21.34万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6642930
• 关键词: angiogenesis; genetically modified animals; laboratory mouse; peroxisome proliferator activated receptor; prostacyclins; prostaglandin endoperoxide synthase; prostaglandin receptor; pulmonary circulation; pulmonary hypertension; vascular smooth muscle

DESCRIPTION (provided by applicant) Severe pulmonary hypertension, including primary pulmonary hypertension (PPH), is an important clinical problem with few clinical treatment options. The chronic, intravenous infusion of prostacyclin (PGI2) has been established as the treatment of choice for patients with PPH. It is now clear that long-term benefits occur which obviate the need for transplant in many cases. The physiological effects of prostacyclin on platelet behavior, vascular tone control, and cell proliferation are well established; however, we do not know whether prostacyclin effects the vascular remodeling in chronic pulmonary hypertension. Our overall hypothesis is that prostacyclin, through membrane-receptor dependent and independent mechanisms, is an important modulator of pulmonary vascular remodeling. We have demonstrated loss of the prostacyclin receptor (PGIR) protein in the smooth muscle cells of precapillary resistance arteries in patients with PPH. We postulate that impairment of the prostacyclin signal transduction contributes to pulmonary vascular remodeling. We have generated transgenic animals with selective pulmonary prostacyclin synthase (PGIS) overexpression. These animals are protected from the development of hypoxic pulmonary hypertension, and show no acute vasoconstriction or chronic vascular remodeling. In contrast, PGIR knockout (KO) mice, in response to hypoxia, develop rapid pulmonary hypertension accompanied by vascular remodeling. Microarray analysis of the lungs from the transgenic animals demonstrates a change in the global pattern of gene expression, which may be responsible for the "protected" phenotype, including changes in PPARs and COX-2. Our underlying concept is that PGI2 exhibits both membrane-receptor mediated and nuclear-receptor-mediated actions. These alternative mechanisms could include direct effects on gene expression, signaling pathways not yet recognized, or changes in the level of other eicosanoids. Our goal is to examine, using both animal models and cell systems, the effects of PGIS and PGIR on vascular smooth muscle cell (VSMO) growth and differentiation. In Specific Aim 1, we will determine whether pulmonary vascular tone and remodeling are mediated through the PGI2 receptor using bitransgenic mice with PGIS overexpression, but lacking PGIR. Specific Aim 2 is designed to define the effect of PGIS and PGIR on the growth and remodeling of vascular smooth muscle cells. The results of this work are designed to elucidate new potential therapeutic targets for treating pulmonary hypertension, and broaden our understanding of vascular pathology in general.

描述（由申请人提供） 严重肺动脉高压，包括原发性肺动脉高压（PPH）， 是一个重要的临床问题，临床治疗选择很少。的 长期静脉输注前列环素（PGI 2）已被确立为 PPH患者的治疗选择。现在很明显，长期 在许多情况下，这些益处会使移植的需要减少。的 前列环素对血小板行为、血管张力的生理作用 控制和细胞增殖已经建立;然而，我们不知道， 前列环素是否影响慢性肺动脉高压患者的血管重构 高血压我们的总体假设是前列环素，通过膜受体 依赖和独立机制，是一个重要的调节剂， 肺血管重构我们已经证明了前列环素的丢失 毛细血管前阻力平滑肌细胞PGIR受体蛋白 PPH患者的动脉。我们假设， 前列环素信号转导参与肺血管重构。 我们已经产生了转基因动物与选择性肺前列环素 合成酶（PGIS）过表达。这些动物受到保护， 缺氧性肺动脉高压的发展，并显示没有急性 血管收缩或慢性血管重塑。相反，PGIR敲除 (KO)小鼠对缺氧的反应是迅速产生肺动脉高压 伴随着血管重塑肺的微阵列分析 转基因动物显示了基因的全球模式的变化， 表达，这可能是负责“保护”表型，包括 PPARs和考克斯-2的变化。我们的基本概念是，PGI 2表现出两种 膜受体介导和核受体介导的作用。这些 替代机制可包括对基因表达的直接影响， 尚未识别的信号通路，或其他信号通路水平的变化， 类花生酸我们的目标是研究，使用动物模型和细胞 系统，PGIS和PGIR对血管平滑肌细胞（VSMO） 生长和分化。在具体目标1中，我们将确定 肺血管张力和重塑通过PGI 2受体介导 使用PGIS过表达但缺乏PGIR的双转基因小鼠。具体 目的2旨在确定PGIS和PGIR对生长和 血管平滑肌细胞的重塑。这项工作的结果是 旨在阐明治疗肺结核的新的潜在治疗靶点， 高血压，并扩大了我们对血管病理学的理解。