Pharmacogenetics of the human prostacyclin receptor.

描述：(申请人提供)：前列环素(PGI2)是花生四烯酸的衍生物，具有促进血管平滑肌松弛和防止血小板聚集的重要作用。这些作用是通过一个鲜为人知的跨膜结构域，跨G蛋白偶联受体(GPCR)，前列环素受体(IP)介导的。这种受体的临床重要性源于它与心血管疾病的关系，如心肌梗死、中风、动脉粥样硬化和高血压。前列环素在治疗肺动脉高压和癌症(结肠癌、乳腺癌和肺癌)中的潜在用途目前正在深入研究中。我们最近发现了11个人类前列环素受体基因的多态性。此外，初步的体外研究发现，这些多态中的一个(R212H)功能异常。这导致了一种假设，即这种多态可能在心血管疾病中发挥关键作用。通过三个具体的目标，这项建议的目标是了解髋关节基因多态性的药物遗传学重要性，并在这样做的过程中确定该受体的独特功能，使其能够结合20碳脂肪酸(二十碳脂肪酸)，并将其耦合到信号转导通路，导致心血管疾病。基因组筛选和测序将被用来全面搜索新的多态并评估与临床心血管疾病的相关性(特定目标1)。将使用定点突变和结构-功能研究(特定目标2)在体外测试所发现的新的多态。具体目标#3将重点放在人类血管平滑肌细胞的下游信号转导通路上，以确定心血管缺陷的机制。除了达特茅斯的药理学、医学(统计学)、血管外科、心脏病学和病理学部门之间的拟议合作外，蛋白质结构功能和信号转导方面的强大团队将是实现这些特定目标的关键资源。这些目标的实现，不仅应该提高我们对前列环素受体的分子遗传学和结构-功能的理解，而且还可能提供关键的生化理解，以解释心血管疾病进展的个体差异和与前列环素类似物治疗相关的各种反应。

DESCRIPTION: (provided by applicant): Prostacyclin (PGI2), a derivative of arachidonic acid, plays an important role promoting vascular smooth muscle relaxation and preventing platelet aggregation. The actions are mediated through a poorly understood seven transmembrane domain spanning G-protein coupled receptor (GPCR), the prostacyclin receptor (IP). The clinical importance of this receptor stems from its involvement in cardiovascular diseases such as myocardial infarction, stroke, atherosclerosis, and hypertension. The potential use of prostacyclin in the treatment of pulmonary hypertension, and cancers (colon, breast and lung), is currently being intensely investigated. We have recently discovered eleven human prostacyclin receptor polymorphisms. Furthermore preliminary in vitro studies have revealed abnormal function in one of these polymorphisms (R212H). This has led to the hypothesis that such polymorphisms may play a critical role in cardiovascular disease. Through three Specific Aims the goal of this proposal is to understand the pharmacogenetic importance of hIP polymorphisms and in so doing to determine distinct features of this receptor, which enable it to bind a 20-carbon fatty acid (eicosanoid) and couple it to signal transduction pathways, leading to cardiovascular disease. Genomic screening and sequencing will be used to comprehensively search for new polymorphisms and assess association with clinical cardiovascular disease (Specific Aim #1). Novel polymorphisms found will be tested in vitro using site-directed mutagenesis, and structure-function studies (Specific Aim #2). Specific Aim #3 will focus on downstream signal transduction pathways in human vascular smooth muscle cells to determine mechanisms for cardiovascular defects. In addition to this proposed collaboration between the Pharmacology, Medicine (Statistics), Vascular Surgery, Cardiology and Pathology Departments here at Dartmouth, strong groups in protein structure-function and signal transduction, will be critical resources for addressing these Specific Aims. Achievement of these aims, should not only improve our understanding of the molecular genetics and structure-function of the prostacyclin receptor, but may also provide the critical biochemical understanding to explain interindividual differences in progress of cardiovascular disease and variable responses associated with prostacyclin analogue treatment.