BETA-2 ADRENERGIC RECEPTOR POLYMORPHISMS AND ASTHMA

描述 （改编自申请人的摘要）这项建议旨在提供 主要研究者（PI）获得知识和技能的机会 在分子生物学和遗传流行病学领域， 两个高素质的共同赞助者，以进一步提高他的潜力， 成为一名独立的调查员。 PI接受临床培训 肺和重症监护医学，并已完成两年的 呼吸流行病学奖学金，除了最近获得了 M.P.H.℃下 该提案的头两年将纳入所需的 课程工作，研讨会和动手实验室的经验，在分子 生物学和遗传技术，使PI能够进行密集的 后三年的研究经验。 整体 这项建议的科学目标是确定β-2肾上腺素能 受体多态性与不同的哮喘表型有关。 的 病例对照设计，嵌套在一个大的，广泛的表型队列中， 被利用。 调查人员建议使用广泛的信息， 气道反应性，支气管扩张剂反应，药物使用，自主神经 神经系统功能，以及过敏和非过敏的标志物 通过对炎症的研究来验证以下假设。 他们假设， B2 AR基因多态性是哮喘发病的重要因素。 他们假设， Arg 16-Gly多态性与气道增加相关， 反应性，对B受体激动剂的反应性降低，更频繁 B受体激动剂和更多的类固醇使用，更大的自主神经功能障碍，更大 过敏性和非过敏性炎症的程度。 他们假设 Gin 27-Glu多态性与气道反应性降低相关， 增强对B-激动剂的反应性，减少B-激动剂和类固醇的频率 使用，减少自主神经功能障碍，减少过敏性和非过敏性炎症。 这项工作的临床益处是，如果一个特定的基因型是 与改变的B-激动剂反应或对B-肾上腺素能 治疗，那么替代治疗方法将指示在这样的 个人，而不必经历一个令人沮丧的失败时期， 对治疗有反应 (End摘要）

DESCRIPTION (Adapted from applicant's abstract) 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. (End of Abstract)