Beta-2 Receptor Polymorphisms and Vasodilation in Humans

描述(由申请人提供)： 这项应用的直接目标是扩大研究人员的科学培训，并为他以患者为导向的研究生涯拓宽基础。职业发展计划将包括以下方面的培训：1)实验设计、实施、统计分析和写作；2)人类研究的伦理行为；3)掌握研究自主神经系统和血管功能的生理学和药理学技术；4)将这些方法与功能基因组学相结合。培训环境将主要是MC GCRC，其中包括导师的实验室和一个配备用于进行本提案中的人体研究的“生理学核心”。迈克尔·乔伊纳博士将担任导师，提供指导和机会，获得在综合心血管生理学方面的丰富经验。研究人员还将与梅奥高血压和内科分部的斯蒂芬·特纳博士合作，后者是高血压遗传基础方面的专家。本申请中的研究部分阐述了β2肾上腺素能受体(B2ADR)的通用多态如何影响人类的血管功能。感兴趣的两个常见多态是核苷酸46和79的错义突变，分别导致氨基酸16和27的变化。在体外，Arg16-Gly替换与激动剂诱导的受体下调有关，而Gln27-Glu替换与抵抗下调有关。这些基因多态性对体内血管功能的影响尚不清楚。为了探索这些问题，研究人员将解决以下具体目标：1)确定常见的β2-ADR基因变异对臂动脉应用b2激动剂后前臂血流反应的影响；2)确定这些β2-ADR基因变异对全身输注β2-激动剂的血流动力学反应的影响；以及3)确定前臂或全身血管扩张反应的差异是否依赖于一氧化氮。我的长期职业目标是成为一名独立的研究员，进行针对人类心血管系统基因组学的生理学和药理学研究。

DESCRIPTION (provided by applicant): The immediate goal of this application is to extend the investigators' scientific training and broaden the foundation for his career in patient-oriented research. The career development plan will include training in: 1) experimental design, conduct, statistical analysis, and writing; 2) ethical conduct in human research; 3) mastery of physiologic and pharmacologic techniques to study the role of the autonomic nervous system and vascular function; and 4) integration of these approaches with functional genomics. The training environment will primarily be the MC GCRC which includes the mentor's laboratory and a "Physiology Core" equipped to conduct the human studies in this proposal. Dr. Michael Joyner will serve as the mentor, providing guidance and opportunities for extensive experience in integrative cardiovascular physiology. The investigator will also collaborate with Dr. Stephen Turner from the Mayo Division of Hypertension and Internal Medicine who is an expert on the genetic basis of hypertension. The research component in this application addresses how generic polymorphisms in beta2-adrenergic receptor (b2ADR) affect vascular function in humans. The two common polymorphisms of interest are missense mutations at nucleotides 46 and 79 that result in changes in amino acids 16 and 27, respectively. In vitro, the Arg 16-Gly substitution, is associated with agonist-induced receptor down-regulation, while the Gln27-Glu substitution is associated with resistance to down-regulation. The effects of these polymorphisms on vascular function in vivo remain unclear. To explore these issues, the investigator will address the following specific aims: 1) to determine the influence of common genetic variations in the beta2-ADR on the forearm blood flow responses to brachial artery administration of b2agonists; 2) to determine the influence of these genetic variations in the beta2ADR on the hemodynamic responses to systemic infusions of beta2-agonists; and 3) to determine if the differences in forearm or systemic vasodilator responses are nitric oxide dependent. My long-term career goals is to become an independent investigator performing physiology and pharmacology studies directed at the genomics of the cardiovascular system in humans.