Prostacyclin Synthase and Receptors in Pulmonary Arterial Hypertension

肺动脉高压中的前列环素合酶和受体

• 批准号: 7824361
• 负责人: MARK W GERACI
• 金额: $ 1.81万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7824361
• 关键词: Abbreviations; Accounting; Affect; Agonist; Biological Models; Blood Pressure; Blood Vessels; Cells; Chromosomal Loss; Complex; CpG Islands; Data; Development; Disease; Down-Regulation; Effectiveness; Endothelial Cells; Endothelin; Epigenetic Process; Epoprostenol; Epoprostenol Receptors; Fluorescent in Situ Hybridization; Frequencies; Gene Expression; Genes; Genetic; Haplotypes; Heart; Human; Hypertension; Hypertrophy; Iloprost; Incidence; Lead; Length; Lesion; Loss of Heterozygosity; Lung; Lung diseases; Mediating; Membrane; Methylation; Minisatellite Repeats; Morbidity - disease rate; Mus; Nuclear; Nuclear Receptors; Onset of illness; Outcome; PPAR Pathway; Pathology; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Persons; Pharmaceutical Preparations; Population; Predisposition; Promoter Regions; Prostacyclin synthase; Prostaglandin-Endoperoxide Synthase; Prostaglandins I; Pulmonary Hypertension; Pulmonary artery structure; Rattus; Relative (related person); Research; Role; Severities; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Smooth Muscle; Transgenic Mice; Transgenic Organisms; Translating; Variant; Vascular remodeling; Woman; Work; analog; blood pump; cell growth; cell type; chromatin immunoprecipitation; combinatorial; human disease; hypertension treatment; improved; inhibitor/antagonist; laser capture microdissection; mouse model; novel; phosphodiesterase V; pre-clinical; pressure; primary pulmonary hypertension; promoter; public health relevance; pulmonary arterial hypertension; receptor; rosiglitazone

DESCRIPTION (provided by applicant): Pulmonary Arterial Hypertension (PAH) is characterized by elevations in pulmonary artery pressure, vascular remodeling, and hyperproliferation of endothelial cells. While there is no cure or preventative treatment for this disease at present, newer targeted therapies can improve outcomes by altering vascular tone using prostacyclin (PGI2) analogues, dual endothelin antagonists, or phosphodiesterase - 5 inhibitors. Recent progress in the understanding of genetic aberrations in PAH suggests that it is a complex disorder and that modifier genes are potentially involved in mediating increased susceptibility and severity. Two genes that affect the level of prostacyclin signaling, prostacyclin synthase (PGIS) and the nuclear receptor PPAR?, are down- regulated in patients with PAH. Disruption of PGI2 signaling through the PPAR? pathway leads to aberrant cell growth. Our hypothesis proposes that PGI2 can signal through either PGIR or PPAR?. We hypothesize that signaling through PGIR results in more prominent effects on vascular tone (RV pressures, RV hypertrophy) while PPAR? stimulation results in more effects on vascular remodeling. The research proposed here focuses on 1) the effectiveness of augmenting signaling through the two different PGI2 receptors as a treatment to reverse remodeling of both smooth muscle and endothelial cells in PAH (PPAR?) or vascular tone (PGIR), 2) the potential modifier gene role of the PGIS and gene in conferring a predisposition to PAH and an increased likelihood of developing severe PAH, and 3) the mechanism of PGIS and PPAR? loss of expression in human disease. We will use two sophisticated murine modeling systems generated by our group to dissect the relative contribution of the two receptors to the development of PAH. Our proposed pre-clinical rat studies establish the effectiveness of a combinatorial treatment using a PGI2 analogue and a PPAR? agonist may quickly translate in to a human combined drug trial. Our preliminary work demonstrates that sequence variation in the proximal PGIS promoter region affects promoter activity leading to low PGIS expression, thus establishing a predisposition to PAH. We will sequence the PGIS promoters from familial pulmonary hypertension, correlating specific haplotypes with disease on-set, severity, and morbidity. Finally, because epigenetic silencing and chromosomal loss are common mechanisms of gene expression down-regulation, we will determine if either is responsible for PGIS or PPAR? down-regulation in micro-dissected PAH lesions using methylation specific PCR (MSP) and fluorescence in situ hybridization (FISH). Specific Aim 1: Delineate the contributions of PGIS and PPAR? pathways to PAH susceptibility and severity. Specific Aim 2: Define transcriptional activity of PGIS promoter sequence variations in relevant primary cells types, and their frequency and correlation in a defined human population. Specific Aim 3: Determine if methylation silencing and/or allelic loss account for PGIS and PPAR? down- regulation in micro-dissected lesions from patients with severe PAH. PUBLIC HEALTH RELEVANCE: Pulmonary Arterial Hypertension (PAH) is a very serious lung disease in which blood pressure in the lung's pulmonary artery increases making the heart work harder to pump blood into the lung. PAH is very rare with an annual incidence of 1 to 2 per million and occurs more often in women. While there is no cure or preventative treatment, newer targeted therapies can improve outcomes. This project will help us understand how current treatments are reducing the changes in the pulmonary artery that lead to the high blood pressure and may lead to newer therapies that are more effective in controlling the progression and severity of PAH.

描述(申请人提供)：肺动脉高压(PAH)的特征是肺动脉压升高、血管重构和内皮细胞过度增殖。虽然目前还没有治愈或预防这种疾病的治疗方法，但较新的靶向治疗可以通过使用前列环素(PGI2)类似物、双重内皮素拮抗剂或磷酸二酯酶-5抑制剂来改变血管张力来改善预后。对PAH遗传异常的最新研究进展表明，PAH是一种复杂的疾病，修饰基因可能参与调节易感性和严重性的增加。两个影响前列环素信号水平的基因，前列环素合成酶(PGIS)和核受体PPAR？，在PAH患者中下调。PPAR对PGI2信号的干扰？途径导致细胞异常生长。我们的假说认为，PGI2可以通过PGIR或PPAR？发出信号。我们假设，通过PGIR传递的信号对血管张力(RV压力、RV肥厚)有更显著的影响，而PPAR？刺激对血管重塑的影响更大。这项研究的重点是：1)通过两种不同的PGI2受体增强信号，逆转PAH(PPAR？)血管内皮细胞重构的有效性。或血管张力(PGIR)，2)潜在的调节基因的作用，使PAH的易感性和发展成严重的PAH的可能性增加，以及3)PGIS和PPAR的机制？在人类疾病中表达的丧失。我们将使用我们小组开发的两个复杂的小鼠模型系统来剖析这两个受体在PAH发展中的相对贡献。我们建议的临床前大鼠研究确定了使用PGI2类似物和PPAR？激动剂可能很快转化为人体联合药物试验。我们的初步工作表明，近端PGIS启动子区域的序列变异影响启动子活性，导致PGIS低表达，从而建立了PAH的易感性。我们将从家族性肺动脉高压中对PGIS启动子进行测序，将特定的单倍型与疾病发生、严重程度和发病率相关联。最后，由于表观遗传沉默和染色体丢失是基因表达下调的常见机制，我们将确定是PGIs还是PPAR？利用甲基化特异性聚合酶链式反应(MSP)和荧光原位杂交(FISH)下调显微解剖的PAH病变中的表达。具体目标1：描述PGIs和PPAR的贡献？PAH易感性和严重性的途径。具体目标2：确定相关原代细胞类型中PGIS启动子序列变异的转录活性，以及它们在特定人群中的频率和相关性。具体目标3：确定甲基化沉默和/或等位基因丢失是否是PGIs和PPAR的原因？重度PAH患者的微小解剖病变中的下调。 公共卫生相关性：肺动脉高压(PAH)是一种非常严重的肺部疾病，其症状是肺的肺动脉血压升高，使心脏更难将血液输送到肺中。帕金森病非常罕见，每年的发病率为1-2‰，女性发病率更高。虽然没有治愈或预防性治疗，但较新的靶向治疗可以改善结果。这个项目将帮助我们了解目前的治疗方法如何减少导致高血压的肺动脉变化，并可能导致更有效地控制PAH的进展和严重程度的新疗法。