Mechanisms of Prostacyclin signaling in Pulmonary Arterial Hypertension

肺动脉高压中前列环素信号传导机制

• 批准号: 7662797
• 负责人: MARK W GERACI
• 金额: $ 22.57万
• 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: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7662797
• 关键词: Accounting; Affect; Biological Models; Blood Vessels; Cells; Chromosomal Loss; CpG Islands; Data; Development; Disease; Down-Regulation; Effectiveness; Endothelial Cells; Endothelin; Enzymes; Epigenetic Process; Epoprostenol; Epoprostenol Receptors; Fluorescent in Situ Hybridization; Frequencies; Gene Expression; Genes; Genetic; Genetic Polymorphism; Haplotypes; Human; Hypertrophy; Hypoxia; Instruction; Length; Lesion; Loss of Heterozygosity; Lung; Mediating; Membrane; Methylation; Minisatellite Repeats; Modeling; Morbidity - disease rate; Mus; Nuclear; Nuclear Receptors; Onset of illness; Outcome; Pathology; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Persons; Population; Predisposition; Promoter Regions; Prostacyclin synthase; Prostaglandins I; Publishing; Pulmonary Hypertension; Pulmonary artery structure; Relative (related person); Role; Severities; Severity of illness; Signal Transduction; Single Nucleotide Polymorphism; Smooth Muscle; Transactivation; Transgenic Mice; Translating; Variant; Vascular remodeling; Work; analog; cell growth; cell type; disorder prevention; human disease; hypertension treatment; improved; inhibitor/antagonist; mouse model; novel; phosphodiesterase V; pre-clinical; pressure; primary pulmonary hypertension; progesterone 11-hemisuccinate-(2-iodohistamine); promoter; pulmonary arterial hypertension; receptor

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 prevention for this disease, newer targetedtherapies can improve outcomes by altering vascular tone using prostacyclin (PGI2) analogues, dual endothelin antagonists, or phosphodiesterase - 5 inhibitors. Recent progress inthe understanding of genetic aberrations in PAH suggests 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 PPARy, are down-regulated in patients with PAH. Disruption of PGI2 signaling through the PPARy pathway leads to aberrant cell growth. Our hypothesis proposes that PGI2 can signal through either PGIR or PPARy. We hypothesize that signaling through PGIR results in more prominent effects on vascular tone while PPARy stimulation results in effects onvascular remodeling. This proposal 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 (PPARY) 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 PPARy 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 preliminary work demonstrates that sequence variation in the proximal PGIS promoter region affects promoter activity leading to low PGIS expression. 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 PPARy 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 PPARy pathwaysto 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 PPARy down-regulation. RELEVANCE (See instructions): We have previously demonstrated that two critical modulators of vascular tone and proliferation (PGI2 and PPAR-/) are downregulated in disease. This application utilizes translational murine modeling to examine mechanisms of signaling important to vasculartone and remodeling. Furthermore, studies of patients with the PAH will be performed to examine the relationship of genetic polymorphisms and disease severity, as well as mechanisms of loss of PGI2 and PPARy.

肺动脉高压（Pulmonary Arterial Hypertension， PAH）以肺动脉压升高为特征