Beta-receptors and cardiovascular pharmacogenomics

β受体和心血管药物基因组学

• 批准号: 6422655
• 负责人: JULIE A. JOHNSON
• 金额: $ 11.44万
• 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/6422655
• 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 描述遗传对药物疗效变异性的贡献， 毒性候选人的重点？的研究计划是确定 β-肾上腺素能受体（β-AR）多态性对药物反应影响 心血管疾病这一广泛的研究目标将在 通过几项研究。第一组研究集中在高血压 (HTN)，其目的是检验β AR基因的假设：a） 与HTN相关; B）是HTN中的疾病修饰，具有特定的焦点 夜间血压下降导致个体 夜间“勺”或“非勺”;和c）是重要的决定因素， 对β受体阻滞剂的降压反应。后一个目标将在一个 小人群，重点是血压，也通过一个 INVEST试验（一项22，000例患者结局试验）的药物遗传学子研究 高血压和有记录的缺血性心脏病患者。的 第二组研究集中在心脏β受体阻滞剂药物遗传学 失败β受体阻滞剂最近被证明可以延长生存期， 减缓心力衰竭患者的疾病进展。这些结果益处是 被认为是与“逆向重塑效应”的 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，以及 心室变成更椭圆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调整。这些研究的重点是 检验β 1 AR的某些多态性是 与β受体阻滞剂的初始耐受性相对较差相关， 也与最戏剧性的影响“逆向重塑”的左 脑室将进行的其他以患者为导向的研究 作为这项研究职业奖的一部分， 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这些研究很重要，因为 它们将增强我们对各种遗传基础的理解， 心血管疾病，并将提供深入了解遗传因素， 影响对作用于β AR的药物的反应。药物遗传学 研究的重要性在于它们可以提供信息， 目标药物靶向最有可能获得 从这种治疗中获得最大的益处，从而导致更好的个性化 和改善病人的治疗效果。这些研究也很重要， 为临床医生提供了极好的研究培训机会。的 建议的研究职业奖是重要的候选人？的职业生涯 这是因为它将提供足够的保护时间， 候选人成功完成正在进行的和计划的研究描述 将加强研究员在新兴领域的培训， 药物基因组学，并将允许候选人的持续增长？S 以病人为导向的研究计划