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（由申请人提供）：肺动脉高压（PAH）的特征是肺动脉压，血管重塑和内皮细胞的过度增殖。尽管目前尚无治愈或预防治疗方法，但使用前列环素（PGI2）类似物，双内皮素拮抗剂或磷酸二酯酶-5抑制剂，可以通过更新的靶向疗法来改善预后。对PAH中遗传畸变的理解的最新进展表明，这是一种复杂的疾病，并且修饰基因可能参与介导增加的敏感性和严重性。 PROSTACYCLIN合酶（PGIS）和核受体PPAR？的两个基因在PAH患者中受调节。通过PPAR的PGI2信号破坏？途径导致细胞生长异常。我们的假设提出PGI2可以通过PGIR或PPAR发出信号。我们假设通过PGIR信号传导会在PPAR时对血管张力（RV压力，RV肥大）产生更突出的影响？刺激会对血管重塑产生更多影响。 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 PGI和PPAR？人类疾病中表达的丧失。我们将使用我们小组生成的两个复杂的鼠建模系统来剖析两个受体对PAH发育的相对贡献。我们提出的临床前大鼠研究确定了使用PGI2模拟和PPAR进行组合治疗的有效性？激动剂可能会迅速转化为人类联合药物试验。我们的初步工作表明，近端PGIS启动子区域的序列变化会影响启动子活性导致PGIS低表达，从而确立了PAH的易感性。我们将从家族性肺动脉高压中对PGIS启动子进行序列，将特定的单倍型与疾病现场，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损失是基因表达下调的常见机制，因此我们将确定是否负责PGI或PPAR？使用甲基化特异性PCR（MSP）和荧光原位杂交（FISH）在微观删除的PAH病变中下调。特定目标1：描述PGI和PPAR的贡献？通往PAH敏感性和严重性的途径。特定目标2：定义相关原代细胞类型中PGIS启动子序列变化的转录活性，以及​​其定义的人口中的频率和相关性。特定目标3：确定甲基化沉默和/或等位基因损失是否解释了PGI和PPAR？严重PAH患者的微截止病变的下调调节。 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，其中肺部肺动脉的血压会增加，使心脏更加努力地将血液泵入肺部。 PAH非常罕见，年龄为每百万美元1至2个，并且在女性中的发生率更高。虽然没有治疗或预防治疗，但较新的靶向疗法可以改善预后。该项目将有助于我们了解当前治疗方法如何减少导致高血压的肺动脉变化，并可能导致更新的疗法，这些疗法在控制PAH的进展和严重程度方面更有效。