Beta-2 Receptor Polymorphisms and Vasodilation in Humans

这次申请的直接目标是扩大我的科学训练，扩大我的基础。 以病人为导向的研究。职业发展计划将包括以下方面的培训： 设计，行为，统计分析和写作，2）人类研究中的道德行为，3）掌握 生理学和药理学技术，研究自主神经系统和血管 功能，以及4）这些方法与功能基因组学的整合。培训环境将 主要是马约诊所GCRC，其中包括导师的实验室和“生理学核心” 有能力进行这项提案中的人体研究。迈克尔·乔伊纳博士将担任导师， 为综合心血管生理学的丰富经验提供指导和机会。我 我还将与马约高血压和内科部的斯蒂芬·特纳博士合作 他是高血压遗传基础方面的专家。该应用程序中的研究组件解决了 132-肾上腺素能受体（_2ADR）的遗传多态性如何影响人类血管功能。的 感兴趣的两种常见多态性是核苷酸46和79处的错义突变，其导致 氨基酸16和27分别发生变化。在体外，Arg 16--_Gly取代与以下相关： 激动剂诱导的受体下调，而Gln27_Glu取代与对 下调。但这些多态性对体内血管功能的影响尚不清楚。到 探讨这些问题，我将解决以下具体目标：1）确定共同的影响力 132-ADRon的遗传变异对肱动脉给予132-ADRon的前臂血流反应的影响。 激动剂，2）确定132 ADRon中这些遗传变异对血流动力学的影响 对132-激动剂全身输注的反应，以及3）确定前臂或全身输注中的差异是否 血管舒张反应依赖于一氧化氮。我的长期职业目标是成为一名独立的 进行针对心血管基因组学的生理学和药理学研究的研究者 人类的系统。

The immediate goal of this application is to extend my scientific training and broaden the foundation for my 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 Mayo Clinic 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. I 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 genetic polymorphisms in the 132-adrenergicreceptor (_2ADR) 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 Argl6--_Gly substitution is associated with agonist-induced receptor down-regulation, while the Gln27_Glu substitution is associated with resistance to down-regulation. But the effects of these polymorphisms on vascular function in vivo remain unclear. To explore these issues, I will address the following specific aims: 1) to determine the influence of common genetic variations in the 132ADRon the forearm blood flow responses to brachial artery administration of 132- agonists, 2) to determine the influence of these genetic variations in the 132ADRon the hemodynamic responses to systemic infusions of 132-agonists,and 3) to determine if the differences in forearm or systemic vasodilator responses are nitric oxide dependent. My long-term career goal is to become an independent investigator performing physiology and pharmacology studies directed at the genomics of the cardiovascular system in humans.