Clinical Effects of Genetic Variability in Adrenergic Receptors

肾上腺素能受体遗传变异的临床影响

• 批准号: 7252845
• 负责人: C M STEIN
• 金额: $ 26.7万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7252845
• 关键词: Adrenergic Agents; Adrenergic Agonists; Adrenergic Receptor; Agonist; Basic Science; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Clinical; Condition; DNA Resequencing; Dexmedetomidine; Dietary Sodium; Disease; Epinephrine; Future; Genes; Genetic; Genetic Variation; Genetically Modified Animals; Genotype; Goals; Haplotypes; Health; Heart failure; Human; Hypertension; Hypoglycemia; Hypotension; In Vitro; Individual; Infusion procedures; Knowledge; Mediating; Methods; Myocardial Infarction; Norepinephrine; Outcome; Pathogenesis; Peripheral; Phenotype; Physiological; Play; Range; Receptor Gene; Regulation; Rest; Risk; Sodium Chloride; Sympathetic Nervous System; Testing; Translating; Variant; adrenergic; base; beta-adrenergic receptor; cardiovascular risk factor; clinical effect; clinically significant; defined contribution; desensitization; genetic variant; human study; in vivo; interest; man; novel; receptor function; response; translational study; vasoconstriction

Project 3:The overall goal of Project 3 is to determine the clinical significance of genetic variation in alpha2- adrenergic receptors (a2-ARs) in humans. The sympathetic nervous system, through alpha and beta adrenergic receptors, is a key regulator of cardiovascular response. Three a2AR subtypes - a2A, a2B, and a2C - are present in humans; studies in genetically modified animals have clarified the function of each subtype. The a2A-AR regulates central inhibition of sympathetic activity, and thus decreases norepinephrine release and blood pressure; the a2B-AR subtype mediates peripheral vasoconstriction and is required for salt-induced increases in blood pressure; the a2C-AR subtype regulates epinephrine concentrations. Recently, genetic variations were described in the human a2A, a2B, and a2C-AR genes, and shown to alter function in vitro. Little is known about the in vivo effects of variation in a2ARs, although some variants have been associated with increased risk of heart failure and myocardial infarction. We have resequenced the human a2A, a2B, and a2C-AR genes, and identified novel variants and defined haplotypes. However, the in vivo functional contribution of these to interindividual differences in sympathetic response, are not known. We will use an approach that has been highly effective in studies of.beta-AR genetic variations, of preselecting healthy individuals with the variants of interest, and studying them under carefully controlled conditions, to determine the relationship of genotype or haplotype with a well-defined phenotype. In Specific Aim 1 we will test the hypothesis that variation in the a2A-AR gene results i) in altered regulation of norepinephrine concentrations in response to physiologic sympathetic activation, and ii) in altered response to stimulation by systemic infusion of the agonist, dexmedetomidine. Specific Aim 2 will test the hypothesis that variation in the a2B-AR gene results in i) altered vascular desensitization in vivo, and ii) altered blood pressure response to salt. Specific Aim 3 will test the hypothesis that variation in the a2C-AR gene alters epinephrine concentrations in response to hypoglycemia. The translational studies proposed will define the contribution of a2-AR subtype genetic variants to physiological and pharmacological responses in vivo, and provide fundamental mechanistic information to guide future targeted studies in cardiovascular disease.

项目 3：项目 3 的总体目标是确定 alpha2- 遗传变异的临床意义 人类肾上腺素能受体（a2-AR）。交感神经系统，通过α和β 肾上腺素能受体，是心血管反应的关键调节剂。三种 a2AR 亚型 - a2A、a2B 和 a2C - 存在于人类中；对转基因动物的研究已经阐明了每种基因的功能 亚型。 a2A-AR 调节交感神经活动的中枢抑制，从而降低去甲肾上腺素 释放和血压； a2B-AR 亚型介导外周血管收缩，并且是 盐引起的血压升高； a2C-AR 亚型调节肾上腺素浓度。 最近，人类 a2A、a2B 和 a2C-AR 基因中的遗传变异被描述，并被证明会改变 体外发挥作用。关于 a2AR 变异的体内影响知之甚少，尽管一些变异已经 与心力衰竭和心肌梗塞的风险增加有关。我们已经重新排序了 人类 a2A、a2B 和 a2C-AR 基因，并鉴定出新的变异和定义的单倍型。然而，在 这些对交感反应个体间差异的体内功能贡献尚不清楚。 我们将使用一种在研究 β-AR 遗传变异、 预先选择具有感兴趣变异的健康个体，并在严格控制下对他们进行研究 条件，以确定基因型或单倍型与明确表型的关系。具体来说 目标 1 我们将检验以下假设：a2A-AR 基因的变异会导致 i) 改变调节 去甲肾上腺素浓度对生理交感神经激活的反应，以及 ii) 改变的反应 通过全身输注激动剂右美托咪定来刺激。具体目标 2 将检验假设 a2B-AR 基因的变异导致 i) 改变体内血管脱敏，以及 ii) 改变血液 对盐的压力反应。具体目标 3 将检验 a2C-AR 基因变异会改变这一假设 肾上腺素浓度对低血糖的反应。拟议的转化研究将定义 a2-AR亚型遗传变异对体内生理和药理反应的贡献，以及 提供基本的机制信息来指导未来心血管疾病的有针对性的研究。