Beta-receptors and cardiovascular pharmacogenomics

β受体和心血管药物基因组学

• 批准号: 6919127
• 负责人: JULIE A. JOHNSON
• 金额: $ 12.25万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919127
• 关键词: beta adrenergic receptor; beta antiadrenergic agent; cardiovascular pharmacology; clinical research; coronary disorder; dosage; drug adverse effect; family genetics; genetic polymorphism; heart failure; human data; human subject; hypertension; obesity; patient oriented research; pharmacogenetics

DESCRIPTION (provided by applicant): Pharmacogenetics/pharmacogenomics is a research field aimed at helping to describe the genetic contribution to variability in drug efficacy and toxicity. The focus of the candidate?s research program is to determine the impact of beta-adrenergic receptor (betaAR) polymorphisms on drug response and cardiovascular disease. This broad research objective will be carried out through several studies. The first set of studies is focused in hypertension (HTN), which aim to test the hypotheses that the betaAR genes: a) are associated with HTN; b) are disease modifying in HTN, with a particular focus on the nocturnal blood pressure decline causing individuals to be either nocturnal "dippers" or "nondippers"; and c) are important determinants of the antihypertensive response to beta-blockers. The latter aim will be tested in a small population, with focus on the blood pressure, and also through a pharmacogenetic substudy of the INVEST trial, a 22,000 patient outcomes trial in patients with hypertension and documented ischemic heart disease. The second group of studies focus on beta-blocker pharmacogenetics in heart failure. Beta-blockers have been recently documented to prolong survival and slow disease progression in heart failure patients. These outcome benefits are thought to be associated with the "reverse remodeling effect" of the beta-blockers on the left ventricle (LV), which result in increases in ejection fraction, reductions in LV wall thickness and mass, and returning the ventricle to a more ellipitical shape. Despite these clear benefits, beta-blockers must be used cautiously during the titration phase to avoid worsening of heart failure, specifically, starting with very low doses, with close monitoring and cautious dose titration. These studies are focused on testing the hypotheses that certain polymorphisms of the beta1AR are associated with relatively poor initial tolerability of beta-blockers, and also with the most dramatic effects of "reverse remodeling" of the left ventricle. Additional patient-oriented research studies that will be conducted as part of this research career award include a study of dobutamine pharmacogenetics, and associations between the PAR genes and obesity or coronary microvascular dysfunction. The proposed studies are important because they will enhance our understanding of the genetic basis of various cardiovascular diseases, and will provide insight into genetic factors that influence response to drugs that act at the betaAR. The pharmacogenetic studies are significant in that they may provide information that will allow the drugs of interest to be targeted to the patients most likely to derive the greatest benefit from such therapy, thus leading to better individualization of therapy, and improved patient outcomes. These studies are also important as they provide excellent research training opportunities for clinicians. The proposed Research Career Award is important to the candidate?s career development in that it will provide sufficient protected time for the candidate to successfully complete the ongoing and planned studies described herein, will enhance the training of fellows in the emerging area of pharmacogenomics, and will allow for the continued growth of the candidate?s patient-oriented research program.

描述(由申请人提供)： 药物遗传学/药物基因组学是一个研究领域，旨在帮助 描述基因对药物疗效和可变性的贡献 毒性。候选人？S研究计划的重点是确定 β-肾上腺素能受体(BetaAR)基因多态性对药物反应和药物代谢的影响 心血管疾病。这一广泛的研究目标将被实施 通过几项研究。第一组研究集中在高血压方面。 (HTN)，旨在测试BetaAR基因的假设：a) 与HTN相关；b)HTN中的疾病修改，具有特定的重点 关于夜间血压下降导致个人要么 夜间的“勺子”或“非勺子”；以及c)是 对β-受体阻滞剂的降压反应。后一个目标将在一个 人口较少，重点关注血压，也通过 INSTEST试验的药物遗传学亚研究，这是一项22,000名患者结果试验 在高血压和有病史的缺血性心脏病患者中。这个 第二组研究集中在心脏中的β-受体阻滞剂药物遗传学 失败了。最近有文献证明，β-受体阻滞剂可以延长生存期和 延缓心力衰竭患者的疾病进展。这些结果的好处是 被认为与“反向重塑效应”有关 左心室(LV)上的β-受体阻滞剂，这会导致 射血分数，左室壁厚度和质量的减少，并返回 脑室变成更椭圆形的形状。尽管有这些明显的好处， 在滴定阶段必须谨慎使用β-受体阻滞剂，以避免 心力衰竭恶化，特别是从非常低的剂量开始， 密切监测和谨慎的剂量滴定。这些研究主要集中在 测试假设：Beta1AR的某些多态是 与β-受体阻滞剂相对较差的初始耐受性有关，以及 同样具有最戏剧性的效果的是左翼的“反向重塑” 脑室。将进行更多以患者为中心的研究 作为这项研究事业奖的一部分，包括对多巴酚丁胺的研究 药物遗传学，以及PAR基因与肥胖或 冠状动脉微血管功能障碍。拟议的研究之所以重要，是因为 它们将加强我们对各种不同基因基础的理解 心血管疾病，并将提供对遗传因素的见解 影响对在BetaAR起作用的药物的反应。药物遗传学 研究具有重要意义，因为它们可能提供的信息将使 感兴趣的药物将针对最有可能产生 从这种治疗中获得最大的好处，从而实现更好的个性化 治疗的效果，并改善患者的预后。这些研究也很重要，因为 它们为临床医生提供了极好的研究培训机会。这个 拟研究职业生涯奖对候选人--S职业生涯很重要 发展，因为它将提供足够的保护时间 成功完成所述的正在进行和计划中的研究的候选人 在此，将加强对以下新兴领域研究员的培训 药物基因组学，会让候选人继续成长吗？S 以病人为中心的研究计划。