Beta-2 Receptor Polymorphisms and Vasodilation in Humans

人类 Beta-2 受体多态性和血管舒张作用

• 批准号: 6557399
• 负责人: JOHN H EISENACH
• 金额: $ 12.03万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6557399
• 关键词: arm; beta adrenergic agent; beta adrenergic receptor; beta antiadrenergic agent; clinical research; family genetics; genetic polymorphism; genotype; hemodynamics; human subject; injection /infusion; nitric oxide; vasodilatation; vasodilation; vasodilators

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.

描述（由申请人提供）： 该应用程序的直接目标是扩展研究人员的科学培训，并为他的以患者为导向的研究而扩大其职业生涯的基础。 职业发展计划将包括：1）实验设计，行为，统计分析和写作； 2）人类研究中的道德行为； 3）掌握生理和药理技术，以研究自主神经系统和血管功能的作用； 4）这些方法与功能基因组学的整合。 培训环境将主要是MC GCRC，其中包括导师的实验室和能够在该建议中进行人类研究的“生理学核心”。 迈克尔·乔伊纳（Michael Joyner）博士将担任这位导师，为综合心血管生理学的丰富经验提供指导和机会。 研究人员还将与高血压遗传基础的专家梅奥高血压和内科医学分部的斯蒂芬·特纳（Stephen Turner）博士合作。 该应用程序中的研究组成部分解决了Beta2-肾上腺素能受体（B2ADR）的通用多态性如何影响人类的血管功能。 感兴趣的两个常见多态性是核苷酸46和79的错义突变，它们分别导致氨基酸16和27的变化。 在体外，Arg 16-替代的体外与激动剂诱导的受体下调有关，而GLN27-GLU取代与对下调的抗性有关。 这些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，研究者将解决以下具体目的：1）确定beta2-ADR中常见遗传变异对前臂血流对臂动脉给药的前臂血流反应的影响； 2）确定这些遗传变异在β2ADR中对β2激动剂全身输注的血流动力学反应的影响； 3）确定前臂或全身血管舒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针对人类心血管系统基因组学的生理学和药理学研究的独立研究者。