Pharmacogenetic Linkage of Corticosteroid Response: Asthma Therapy Implications

描述（由申请人提供）：该指导以患者为导向的职业发展奖将为主要研究者（PI）提供哮喘患者基因组研究方面的知识，技能和专业知识，重点是哮喘治疗的药物遗传学。PI接受过儿科和成人肺病学培训，并在Channing实验室完成了呼吸流行病学研究，同时获得了哈佛公共卫生学院的MPH。他目前还经营着一家儿科哮喘诊所。进一步的培训和研究将在一个高素质的咨询委员会的监督下进行，该委员会具有哮喘流行病学和临床研究，分子生物学，遗传流行病学和统计学方面的专业知识，并将包括课程工作，动手遗传实验室经验和患者招募。 该奖项将促进药物基因组学应用于患者护理的成功独立研究事业的发展。本研究的总体科学目标是研究儿童哮喘患者皮质类固醇诱导的细胞表达变化与临床结局的关系。我们假设家族内皮质类固醇基因表达反应可作为哮喘患者吸入性皮质类固醇反应的生物标志物，并确定与之相关的新基因组区域。我们试图通过评估哮喘患者对吸入性皮质类固醇的临床反应来研究这一假设，作为对以下结果的反应：a）皮质类固醇诱导的细胞表达变化本身，B）与表达变化相关的区域中的位置候选基因，以及c）随皮质类固醇给药而显著变化的表达候选基因。每一项研究都将使用来自一组儿童哮喘患者的细胞系、DNA和表型特征来完成，PI将与这些患者直接互动并积极随访。通过对该项目细节的实际关注，PI将深入了解当前的分子，遗传和统计方法，并为以患者为导向的研究奠定坚实的基础。该奖项的成功完成将提供必要的背景，开始在翻译药物基因组学的独立职业生涯。

DESCRIPTION (provided by applicant): This Mentored Patient-Oriented Career Development Award will provide the Principal Investigator (PI) with knowledge, skills, and expertise in the genomic study of patients with asthma with an emphasis on the pharmacogenetics of asthma therapy. The PI is trained in pediatric and adult pulmonology and has completed his fellowship in respiratory epidemiology at the Channing Laboratory, concurrently receiving his MPH from the Harvard School of Public Health. He also currently runs a pediatric asthma clinic. Further training and research will be carried out under the supervision of a highly qualified advisory committee, with expertise in asthma epidemiology and clinical studies, molecular biology, genetic epidemiology, and statistics, and will include course work, hands-on genetic laboratory experience, and patient recruitment. This award will facilitate the development of a successful independent research career in the application of pharmacogenomics to patient care. The overall scientific goal of this proposal is to investigate the relationship of cellular corticosteroid induced expression changes to clinical outcomes in childhood asthmatics. We hypothesize that corticosteroid gene expression response within families will serve as biomarkers of, and identify novel genomic regions associated with, the response to inhaled corticosteroids in asthma. We seek to investigate this hypothesis by evaluating the clinical response to inhaled corticosteroids in asthma as an outcome in response to a) corticosteroid induced cellular expression changes themselves, b) positional candidate genes in regions linked to the expression changes, and c) expression candidate genes that significantly vary with corticosteroid administration. Each of these will be accomplished using cell lines, DNA, and phenotypic characteristics from a cohort of childhood asthmatics with whom the PI will directly interact and actively follow. Through the practical attention to the details of this project, the PI will garner a thorough understanding of current molecular, genetic, and statistical methods, as well as develop a solid foundation for patient-oriented research. Successful completion of this award will provide the necessary background to commence an independent career in translational pharmacogenomics.