Beta2-Adrenergic Receptor Gene Variation and Cardiovascular Control in Humans

人类β2-肾上腺素能受体基因变异与心血管控制

基本信息

批准号：
8235941
负责人：
JOHN H EISENACH
金额：
$ 37.4万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8235941
关键词：
AR gene Ablation Address Adrenergic Receptor Affect Affinity Agonist Amino Acids Arginine Baroreflex Binding Blood Circulation Blood Vessels Cardiac Cardiac Output Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Caucasians Caucasoid Race Code Data Development Diet Dietary Sodium Ethnic Origin Exercise Forearm Genes Genetic Genetic Variation Glutamates Glutamine Glycine Goals Haplotypes Heart Human Hypertension Individual Infusion procedures Inherited Intake Isometric Exercise Laboratories Low Cardiac Output Lymphocyte Mediating Molecular Conformation Nitric Oxide Outcome Pathogenesis Peripheral Resistance Pharmaceutical Preparations Pharmacogenetics Phenotype Physiological Positioning Attribute Production Protocols documentation Psyche structure Race Receptor Gene Regulation Resolution Role Single Nucleotide Polymorphism Sodium Stress Stroke Volume Testing Variant Vasodilation Vasodilator Agents base beta-2 Adrenergic Receptors blood pressure regulation cohort improved insight interest public health relevance receptor response trait volunteer young adult

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this A1 resubmission is to advance the understanding of human ¿2-adrenergic receptor (¿2-AR) gene haplotype variation and cardiovascular phenotype. An emerging but yet to be defined relationship exists in humans between ¿2-AR haplotype, the pressor response to sympathoexcitatory maneuvers like mental stress and handgrip, ¿2-mediated cardiac and vascular function, and dietary sodium manipulation. Single nucleotide polymorphisms (SNP's) encoding the 16th and 27th amino acid in the ¿2- AR gene have been characterized in combination, whereas the need exists to examine the functional relevance of the three, most common haplotypes in an ethnically homogenous cohort, thus controlling for variation in SNP's and race/ethnicity. Our strategy is to perform hypothesis-driven protocols with respect to ¿2-AR haplotype on physiological and pharmacological responses pertinent to the pathogenesis of hypertension and cardiovascular disease in Caucasians. In AIM 1 we test whether individuals homozygous for common haplotypes in the ¿2-AR influence the cardiovascular and regional vasodilator responses to sympathoexcitatory maneuvers following a normal sodium diet. We hypothesize that healthy individuals carrying the haplotype homozygous for glycine at position 16 (Gly16) and glutamate at position 27 (Glu27) (haplotype 1) will demonstrate greater cardiac output and lower systemic vascular resistance during mental stress and isometric handgrip exercise than individuals with haplotypes homozygous for arginine (Arg16) + glutamine (Gln27) (haplotype 2) and Gly16 + Gln27 (haplotype 3). In AIM 2 we test whether common haplotypes in ¿2-AR influence the cardiovascular and regional vasodilator responses to sympathoexcitatory maneuvers after 5 days of dietary sodium restriction, followed by 5 days of dietary sodium loading. We hypothesize the greater cardiac output and systemic ¿2-AR mediated vasodilation in haplotype 1 following normal dietary sodium intake will no longer be seen following dietary sodium restriction, and these responses will be augmented following sodium loading. In AIM 3 we test whether common haplotypes in ¿2- AR influence the cardiovascular and regional vasodilator responses to systemic infusions of ¿2-AR agonist, after temporary pharmacological ablation of baroreflex control of the circulation. We hypothesize a) that after baroreflex ablation, the haplotype 1 will be associated with greater cardiac output and greater systemic ¿2-AR mediated vasodilation than haplotypes 2 and 3 during systemic ¿2-AR agonist infusion; b) that effects of ¿2- AR haplotype variation on systemic vascular resistance will be dependent on ¿2-AR mediated production of nitric oxide. Finally, we hypothesize that ex vivo determination of lymphocyte ¿2-AR's present in the high affinity binding conformation will mechanistically explain the influence of dietary sodium manipulation on haplotype-dependent differences in cardiovascular function. The mechanistic high-resolution phenotyping in this proposal will provide important new genetic insight about the pathogenesis of cardiovascular disorders. PUBLIC HEALTH RELEVANCE The overall goal of this project is to advance the understanding of how genetic variation in a major heart and blood vessel receptor (the beta-2 adrenergic receptor) influences cardiovascular regulation. Healthy young adult volunteers will be grouped according to diverse yet commonly inherited forms of the beta-2 receptor. By determining the genetic influence of blood pressure regulation in response to stressful maneuvers, medication infusions, and dietary sodium intake, this strategy will provide mechanistic detail of how genes interact with intermediate physiological traits pertinent to the development of hypertension and cardiovascular disease.

描述（由应用程序提供）：该A1重新提交的总体目标是促进对人类2-肾上腺素能受体（2-AR）基因单倍型变异和心血管表型的理解。人类之间存在着一种新兴但尚未定义的关系，在2-AR单倍型之间，对交感神经动作（如精神压力和手夹）的施加反应，»2介导的心脏和血管功能以及饮食中的钠钠操纵。已经表征了编码第16和第27氨基酸的单个核肽多态性（SNP）的组合表征，而存在需要检查三种（最常见的单倍型）在族裔同种群中的功能相关性的需要，从而控制了SNP和种族/族裔的差异。我们的策略是针对与高加索人的高血压和心血管疾病的发病机理有关的2AR单倍型执行假设驱动的方案。在AIM 1中，我们测试了2-AR中常见单倍型的个体是否会影响正常钠饮食后的副电心兴奋性动作的心血管和区域血管扩张剂的反应。 We hypothesize that healthy individuals carrying the haplotype homozygous for glycine at position 16 (Gly16) and glutamate at position 27 (Glu27) (haplotype 1) will demonstrate greater cardiac output and lower systemic vascular resistance during mental stress and isometric handgrip exercise than individuals with haplotypes homozygous for arginine (Arg16) + glutamine (Gln27) （单倍型2）和Gly16 + GLN27（单倍型3）。在AIM 2中，我们测试了2-AR中的常见单倍型是否影响心血管和区域血管扩张剂对饮食中的饮食钠限制5天后对交感神经兴奋性动作的反应，然后进行5天的饮食钠负荷。我们假设在饮食钠限制后，正常饮食钠摄入后，将不再看到更大的心输出量和全身性»单倍型1中2-AR介导的血管舒张，并且在钠负荷后将增加这些反应。在AIM 3中，我们测试2-AR中的常见单倍型是否影响心血管和区域血管扩张剂对循环循环的临时药物消融后，对2-AR激动剂的全身输注的反应。我们假设a）a）在压力反射消融后，单倍型1将与更大的心输出量和更大的全身性»2-AR介导的血管舒张相比，在全身性»2-AR激动剂输注过程中，单倍型2和3； b）€2-AR单倍型变化对全身血管耐药性的影响将取决于2-AR介导的一氧化氮产生。最后，我们假设在高亲和力结合构象中存在的淋巴细胞的体外测定将机械解释饮食中钠操纵对心血管功能单倍型依赖性差异的影响。该提案中的机械高分辨率表型将提供有关心血管疾病发病机理的重要新遗传见解。公共卫生相关性该项目的总体目标是提高对主要心脏和血管受体（β-2肾上腺素能受体）中遗传变异的理解，从而影响心血管调节。健康的年轻成人志愿者将根据潜水员但通常遗传的β-2受体形式进行分组。通过确定血压调节的遗传影响，响应压力性手术，药物输注和饮食钠的摄入量，该策略将提供有关基因如何与与高血压和心血管疾病发展有关的中间物理特征相互作用的机械细节。