BETA-2 ADRENERGIC RECEPTOR POLYMORPHISMS AND ASTHMA

描述 (改编自申请人的摘要)本建议旨在提供 首席调查员(PI)获得知识和技能的机会 在分子生物学和遗传流行病学方面，在直接监督下 两位高素质的联合发起人，以进一步增强他的潜力 发展成为一个独立的调查者。PI在临床上进行了培训 肺部和重症监护医学，已经完成了两年的 呼吸流行病学奖学金，除了最近获得 每小时最高学位。这项提案的头两年将纳入所需的 分子方面的课程工作、研讨会和动手实验室经验 生物和遗传技术使PI能够进行密集的 建议后三年的研究经验。整体而言 这项提议的科学目标是确定β-2肾上腺素能 受体基因多态性与不同的哮喘表型有关。这个 病例对照设计，嵌套在一个大的、广泛表型的队列中 被利用。调查人员建议利用这些广泛的信息 呼吸道反应性、支气管扩张剂反应、用药、自主神经 神经系统功能及过敏和非过敏标志物 炎症来检验以下假说。他们假设没有 B2AR基因多态性是哮喘的主要致病因素。他们假设 Arg16-Gly基因多态与呼吸道增加相关 反应性，对B-激动剂的抑制反应性，更频繁 B-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 Gin27-Glu基因多态性与呼吸道反应性降低相关， 增强对B受体激动剂、较少使用B受体激动剂和类固醇的反应性 使用，较少自主神经功能障碍，较少过敏性和非过敏性炎症。 这项工作的临床好处是，如果特定的基因型是 与B-激动剂反应改变或对B-肾上腺素能耐药相关 治疗，那么将在这种情况下指示替代治疗方法 个人不需要经历一段令人沮丧的失败时期 对治疗有反应。(摘要结束)

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)