Pharmacogenetic Linkage of Corticosteroid Response: Asthma Therapy Implications

描述（由申请人提供）：这个以患者为导向的职业发展奖将为首席研究员（PI）提供哮喘患者基因组研究的知识、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方面的培训，并在Channing实验室完成了呼吸流行病学的研究，同时在哈佛大学公共卫生学院获得了公共卫生硕士学位。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专业知识的高素质咨询委员会的监督下进行，并将包括课程作业、实践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方面的成功独立研究事业的发展。本提案的总体科学目标是研究皮质类固醇诱导的细胞表达变化与儿童哮喘临床结局的关系。我们假设家族内的皮质类固醇基因表达反应将作为哮喘患者吸入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吸入皮质类固醇的临床反应来研究这一假设，作为a)皮质类固醇诱导的细胞表达改变本身的结果，b)与表达变化相关区域的位置候选基因，以及c)随着皮质类固醇给药而显著变化的候选基因。每一项研究都将利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跟踪。通过对该项目细节的实际关注，PI将对当前的分子，遗传和统计方法有透彻的了解，并为以患者为导向的研究奠定坚实的基础。这个奖项的成功完成将提供必要的背景，开始在转化药物基因组学独立的职业生涯。

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.