This proposal seeks to provide the opportunity for the Principal Investigator (PI) to gain knowledge and skills in molecular biology and genetic epidemiology, under the direct supervision of two highly qualified co-sponsors, to further enhance his potential to develop into an independent investigator. The PI is trained in clinical Pulmonary and Critical Care Medicine and has completed two years of a respiratory epidemiology fellowship, in addition to recently obtaining a M.P.H. degree. The first two years of this proposal will incorporate needed course-work, seminars, and hands-on laboratory experience in molecular biology and genetic techniques to enable the PI to undertake an intensive research experience in the latter three years of the proposal. The overall scientific goal of this proposal is to determine whether beta-2 adrenergic receptor polymorphisms are related to different asthma phenotypes. The case-control design, nested in a large, extensively phenotyped cohort will be utilized. The investigators propose to use the extensive information on airway reactivity, bronchodilator response, medication use, autonomic nervous system function, and markers of allergic and non-allergic inflammation to test the following hypotheses. They hypothesize that no B2AR polymorphism is a major causal factor of asthma. They hypothesize that the Arg16-Gly polymorphism is associated with increased airway responsiveness, depressed responsiveness to B-agonists, more frequent B-agonist and greater steroid use, greater autonomic dysfunction, greater degree of allergic and non-allergic inflammation. They hypothesize that the Gin27-Glu polymorphism is associated with decreased airway responsiveness, enhanced responsiveness to B-agonists, less frequent B-agonist and steroid use, less autonomic dysfunction, less allergic and nonallergic inflammation. The clinical benefit of this work is that if a particular genotype is associated with altered B-agonist response or resistance to B-adrenergic therapy, then alternative therapeutic approaches would be indicated in such individuals without having to go through a frustrating period of failure to respond to therapy.
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