Prostacyclin synthase and prostacyclin receptor in PH

描述(由申请人提供) 严重的肺动脉高压，包括原发性肺动脉高压(PPH)， 是一个重要的临床问题，几乎没有临床治疗选择。这个 慢性静脉输注前列环素(PGI2)已被证实为 PPH患者的治疗选择。现在很明显，长期的 好处出现了，在许多情况下消除了移植的需要。这个 前列环素对血小板行为、血管紧张性的生理影响 控制和细胞增殖已经确立；然而，我们不知道 前列环素对慢性肺血管重构的影响 高血压。我们的总体假设是前列环素通过膜受体 依赖和独立的机制，是一个重要的调节器 肺血管重塑。我们已经证实前列环素的丢失 毛细血管前阻力血管平滑肌细胞中的受体(PGIR)蛋白 PPH患者的动脉。我们假设减损 前列环素信号转导参与肺血管重塑。 我们已经产生了选择性肺前列环素的转基因动物 合酶(PGIs)过表达。这些动物受到保护，不受 发展为缺氧性肺动脉高压，且无急性 血管收缩或慢性血管重塑。相比之下，PGIR基因敲除 (KO)小鼠对低氧作出反应，形成快速的肺动脉高压 伴随着血管重塑。肺组织的微阵列分析 转基因动物表明全球基因模式发生了变化 表达，这可能是“受保护”表型的原因，包括 PPAR和COX-2的变化。我们的基本概念是PGI2既表现出 膜受体介导和核受体介导的作用。这些 替代机制可能包括对基因表达的直接影响， 尚未被识别的信号通路，或其他水平的变化 二十烷类化合物。我们的目标是研究，使用动物模型和细胞 PGIs和PGIR对血管平滑肌细胞(VSMO)的影响 生长和分化。在具体目标1中，我们将确定是否 肺血管张力和重塑是通过PGI2受体介导的 使用Pgis高表达但缺乏PgIR的双转基因小鼠。特定的 AIM 2旨在定义PGIs和PGIR对生长和 血管平滑肌细胞重塑。这项工作的结果是 旨在阐明治疗肺癌的新的潜在治疗靶点 高血压，并拓宽了我们对血管病理的一般理解。

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.