Beta-2 Receptor Polymorphisms and Vasodilation in Humans

超出所提供的空间。这个申请的直接目标是扩展我的科学训练，拓宽我在病人导向研究方面的职业基础。职业发展计划将包括以下方面的培训：1)实验设计、操作、统计分析和写作；2)人类研究中的伦理行为；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的作用；4)将这些方法与功能基因组学相结合。培训环境将主要是梅奥诊所GCRC，其中包括导师的实验室和“生理学核心”，以进行本提案中的人体研究。Michael Joyner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。我还将与梅奥高血压和内科的Stephen Turner医生合作，他是高血压遗传基础方面的专家。本应用程序的研究部分解决了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。两种常见的多态性是核苷酸46和79的错义突变，分别导致氨基酸16和27的变化。在体外，Argl6- _Gly取代与激动剂诱导的受体下调有关，而Gln27_Glu取代与抗下调有关。但这些多态性对体内血管功能的影响尚不清楚。为了探讨这些问题，我将解决以下具体目标：1)确定132ADRon中常见遗传变异对肱动脉给药132-激动剂后前臂血流反应的影响，2)确定132ADRon中这些遗传变异对全身输注132-激动剂后血流动力学反应的影响，以及3)确定前臂或全身血管扩张剂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者，从事人类心血管系统基因组学方面的生理学和药理学研究。PERFORMANCESITE ( ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. 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. PERFORMANCESITE( ========================================Section End===========================================