Pharmacogenetics of the human prostacyclin receptor.

描述(申请人提供)：随着人口日益老龄化，估计79,400,000受影响个人的心血管疾病管理费用将占我们卫生预算的越来越大的比例。对风险最高的人群及早识别和干预可能有助于降低相关发病率和死亡率。人类前列环素受体最近被发现与基因敲除小鼠研究和环氧合酶-2抑制剂临床试验(如万络)有关，它们在抑制动脉粥样硬化和血栓形成方面具有重要作用，而动脉粥样硬化和血栓形成是导致心血管疾病的两个主要原因。基于这些观察，我们假设人类前列环素受体自然发生的基因突变可能使个人更容易患上疾病。我们最近从1,434名心血管患者和对照患者中筛选出了31个人类前列环素受体的遗传变异。我们的假设是，这些变异与心血管疾病的临床进展有关。通过三个特定的目标，我们建议在多个水平上研究野生型和变异型受体。分子和生化研究(具体目标1)将剖析人类前列环素受体的结构和功能，确定结合和激活所需的关键结构成分，以及这些变异可能如何影响这些结构成分。根据患者的临床数据(特定目标2)，我们将把基因变异与冠状动脉疾病(动脉粥样硬化)的发展联系起来。此外，我们还将把重点放在非洲裔美国人群体上，在那里我们发现了一些位于高度保守位置的潜在重要变异。第三个特殊目的来自我们的初步观察，即血管平滑肌细胞具有前列环素诱导的前列环素释放(正反馈)机制，该机制在防止旁分泌方式的增殖和去分化(导致再狭窄和内膜增生)方面似乎是重要的。这似乎在很大程度上独立于已知的前列环素受体蛋白激酶A信号通路。将深入探索通过ERK和Akt发出新信号所需的初步证据。为了确保我们的研究采用彻底、细致、准确和符合伦理的方法，我们将与我们的机构审查委员会、计算遗传学实验室、生物统计学家、心脏病科和血管外科密切合作进行研究。在这个“后基因组时代”，我们现在准备通过对遗传变异的研究，对前列腺素受体的结构和功能以及它们与心血管疾病的关系提出关键的见解。 公共卫生相关性：心血管疾病仍然是美国发病率和死亡率的最大原因。随着最近人类基因组测序的完成，我们现在准备揭开许多导致心血管疾病的易感基因。我们有强有力的证据表明，前列环素受体及其信号通路将在预防动脉粥样硬化中发挥关键作用，因此，功能失调的基因变异将使患者更容易患上加速性疾病。

DESCRIPTION (provided by applicant): With a progressively aging population, the cost of managing cardiovascular disease among the estimated 79,400,000 affected individuals will account for increasing proportions of our health budget. Early identification and intervention in those at greatest risk may assist in reducing the associated morbidity and mortality. The human prostacylin receptor has recently been implicated in knockout mice studies, and cyclooxygenase-2 inhibitor clinical trials (e.g. Vioxx(tm)), as important in inhibiting atherosclersosis and thrombosis, two major causes of cardiovascular disease. Based upon these observations, we hypothesize that naturally occurring genetic mutations in the human prostacyclin receptor may predispose individuals to disease. We have recently identified 31 genetic variants of the human prostacyclin receptor from screening 1,434 cardiovascular and control patients. Our hypothesis is that such variants are associated with clinical progression of cardiovascular disease. Through three specific aims we propose to study the wild type and variant receptors at multiple levels. Molecular and biochemical studies (Specific Aim 1) will dissect the structure and function of the human prostacyclin receptor determining the critical structural components required for binding and activation and how these may be influenced by the variants. With the patients' clinical data (Specific Aim 2), we will correlate genetic variants to the development of coronary artery disease (atherosclerosis). A focus will additionally be placed on the African American population where we have uncovered some potentially important variants located at highly conserved positions. The third Specific Aim has arisen from our preliminary observation that vascular smooth muscle cells have a prostacyclin induced prostacyclin release (positive feedback) mechanism which appears to be important in preventing proliferation and dedifferentiation (cause of restenosis and intimal hyperplasia) in a paracrine fashion. This appears to be largely independent of the known prostacyclin receptor protein kinase A signaling pathway. Preliminary evidence that novel signaling through ERK and Akt is required will be intensively explored. To ensure a thorough, meticulous, accurate, and ethical approach to our studies, they will be conducted in close collaboration with our Institutional Review Board, Computational Genetics Laboratory, Biostatistician, Cardiology Department, and Vascular Surgery Department. In this "postgenomic era" we are now poised to develop critical insights into the structure and function of the prostanoid receptors and their relationship to cardiovascular disease, through the study of genetic variants. PUBLIC HEALTH RELEVANCE: Cardiovascular disease remains the single greatest cause of morbidity and mortality in the USA. With the recent sequencing of the human genome we are now poised to uncover many of the predisposing genetic contributors to cardiovascular disease. We have strong evidence that the prostacyclin receptor and its signaling pathways will play a critical role in the prevention of atherosclerosis, and as such, dysfunctional genetic variants will predispose patients to accelerated disease.