Pharmacogenetics of the human prostacyclin receptor.

6.项目摘要/摘要 随着人口的逐渐老龄化，在估计的 79,400,000受影响的个人将占我们卫生预算的越来越大的比例。早些时候 对风险最高的人群进行识别和干预，可能有助于减少相关的发病率和 死亡率。人类前列环素受体最近被发现与基因敲除小鼠的研究有关，而且 环氧合酶-2抑制剂临床试验(如万络“)，作为重要的抑制动脉粥样硬化和 血栓形成是心血管疾病的两个主要原因。基于这些观察结果，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体更容易患上 疾病。我们最近从筛查中鉴定出31个人类前列环素受体的遗传变异 1434名心血管疾病患者和对照患者。我们的假设是，这些变异与临床 心血管疾病的进展。通过三个具体目标，我们建议研究野生型和 在多个水平上的变异受体。分子和生化研究(特定目标1)将剖析 决定关键结构成分的人前列环素受体的结构和功能 结合和激活所需的，以及它们可能如何受变体的影响。与病人的 临床数据(特定目标2)，我们将把基因变异与冠状动脉的发展联系起来 疾病(动脉粥样硬化)。我们还将把重点放在非洲裔美国人身上 已经发现了一些位于高度保守位置的潜在重要变体。第三个具体问题 我们的初步观察表明，血管平滑肌细胞有一种前列环素- 诱导前列环素释放(正反馈)机制，似乎在预防 旁分泌方式的增殖和去分化(导致再狭窄和内膜增生)。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传递新信号所需的初步证据。至 确保对我们的研究采取彻底、细致、准确和符合道德的方法，这些研究将在 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、 心内科、血管外科。在这个“后基因组时代”，我们现在正准备 对前列腺素受体的结构和功能及其与 心血管疾病，通过对遗传变异的研究。

6. PROJECT SUMMARY/ABSTRACT 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"), 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.