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.
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