Pharmacogenetics of Beta2-Agonists in Asthma

描述(由申请人提供)： 候选人是一位资深研究科学家，他领导了一个成功的行业赞助的哮喘临床试验计划长达15年之久。她希望将她的职业生涯从行业赞助的研究过渡到研究人员发起的哮喘药物遗传学研究，并成功地竞争资金。她的研究兴趣是确定患者之间对哮喘药物反应差异的遗传原因。为了实现她的职业目标，她将接受分子生物学、遗传学、流行病学、统计学和资历方面的课程和培训。她将由哮喘药物遗传学、统计遗传学、肺部流行病学、药物靶标药物遗传学和分子生物学的专家科学家指导。她将完成一个有两个具体目标的研究项目。具体目的1：确定高加索人和非裔美国人中p2肾上腺素能受体(P2 AR)通路基因多态性与沙丁胺醇的支气管扩张剂反应之间的关系；特定目的2：确定p2受体基因多态在高加索和非裔美国人沙美特罗治疗后p2受体激动剂促进脱敏中的作用。具体目标1将通过从美国肺协会哮喘临床研究中心网络试验期间获得的现有DNA集合中对p2 AR途径候选基因上的30多个单核苷酸多态进行基因分型来实现，并分析这些遗传变异与沙丁胺醇的支气管扩张剂反应之间的关联。具体目标2将在一项临床研究中完成，以确定哪些具有特定p2AR二倍型的患者对沙美特罗引起的脱敏敏感；脱敏效果将通过乙酰甲胆碱激发试验和支气管扩张剂对沙丁胺醇的反应来衡量。这项建议将为研究人员发起的哮喘药物遗传学研究做好准备，结果可能允许临床医生使用药物遗传学数据来选择适当的短效和长效p2激动剂治疗哮喘。 (摘要结束)

DESCRIPTION (provided by applicant): The candidate is a senior research scientist who has directed a successful industry sponsored asthma clinical trials program for 15 years. She desires to transition her career from industry sponsored research to investigator-initiated research in asthma pharmacogenetics and successfully compete for funding. Her research interest is to determine the genetic causes for inter-patient differences in the response to asthma drugs. To achieve her career goal, she will have coursework and training in molecular biology, genetics, epidemiology, statistics, and grantsmanship. She will be guided by expert scientists in asthma pharmacogenetics, statistical genetics, pulmonary epidemiology, drug target pharmacogenetics, and molecular biology. She will complete a research project with 2 specific aims. Specific Aim 1: to determine associations between p2 adrenergic receptor (P2 AR) pathway polymorphisms and bronchodilator response to albuterol in Caucasians and African Americans; Specific Aim 2: to determine the role of selected p2 AR polymorphisms in p2-agonist promoted desensitization following treatment with salmeterol in Caucasians and African Americans. Specific Aim 1 will be accomplished by genotyping over 30 single nucleotide polymorphisms on p2 AR pathway candidate genes from an extant collection of DNA obtained during an American Lung Association Asthma Clinical Research Centers network trial and analyze associations between the genetic variants and bronchodilator response to albuterol. Specific Aim 2 will be accomplished in a clinical study to determine which patients with specific p2 AR diplotypes are susceptible to desensitization caused by salmeterol; desensitization effects will be measured by methacholine challenge testing and bronchodilator response to albuterol. This proposal will prepare the candidate for investigator initiated research in asthma pharmacogenetics and results may allow clinicians to use pharmacogenetic data to select appropriate short- and long-acting p2agonist therapy in asthma. (End of Abstract)