INTEGRATIVE GENOMICS AND THE FETAL ORIGINS OF IMPAIRED LUNG FUNCTION

描述（由申请人提供）：慢性阻塞性呼吸系统疾病，包括慢性阻塞性肺疾病（COPD）和哮喘，是全球发病率和死亡率的主要原因之一。肺功能是一个独立的生存预测指标，也是哮喘和COPD疾病严重程度的特定标志。从出生后不久到成年，肺功能的测量沿着类似的百分位数曲线进行，这表明肺发育的遗传程序和子宫内暴露是以后生活中肺功能的关键决定因素。新疗法的发展需要一个全面的可修改的遗传靶点和分子途径的目录，这些途径有助于易感人群肺功能受损的发展和进展。包括表达微阵列和高通量基因分型平台在内的基因组技术为推进这一进程提供了前所未有的机会。“整合基因组学”旨在将基因型数据与基因表达数据结合起来，以更快地识别与基因功能有关的位点。该项目的首要前提是培养主要研究者将基因表达与早期人类肺发育的基因型数据相结合，以确定哮喘和COPD患者肺功能受损的关键发育调节变异和生物学途径。我们已经概述了一系列的课程，将允许主要研究者应用综合基因组方法对人类胎儿肺发育。这个项目的成功将促进主要研究者过渡到呼吸基因组学的独立研究。此外，该项目的结果可能会导致阻塞性呼吸系统疾病患者的新疗法的发展。

DESCRIPTION (provided by applicant): Chronic obstructive respiratory diseases, including both chronic obstructive pulmonary disease (COPD) and asthma, are among the leading causes of morbidity and mortality worldwide. Pulmonary function is an independent predictor of survival, as well as a specific marker of disease severity in asthma and COPD. Measures of pulmonary function track along similar percentile curves from shortly after birth into adulthood, suggesting that the genetic programming of lung development and in utero exposures are critical determinants of lung function later in life. The development of novel therapies requires a comprehensive catalog of modifiable genetic targets and the molecular pathways that contribute to the development and progression of impaired lung function in susceptible populations. Genomic technologies including expression microarrays and high-throughput genotyping platforms offer an unprecedented opportunity to advance this process. "Integrative genomics" seeks to combine genotype data with gene expression data to more rapidly identify loci contributing to the function of a gene. The overarching premise of this project is to train the primary investigator to combine gene expression with genotypic data of early human lung development to identify critical developmental regulatory variants and the biologic pathways that contribute to the development and progression of impaired lung function in asthma and COPD. We have outlined a series of courses that will allow the primary investigator to apply an integrative genomic approach to human fetal lung development. Success in this project will foster the primary investigator's transition to independent research in respiratory genomics. Furthermore, results of this project could lead to the development of novel therapies for patients with obstructive respiratory diseases. PUBLIC HEALTH RELEVANCE: Chronic obstructive respiratory diseases, including both asthma and chronic obstructive pulmonary disease (COPD), are among the leading causes of morbidity and mortality, resulting in over $45 billion in annual healthcare costs in the US alone. A better understanding of the biologic pathways that influence lung function impairment may identify innovative therapeutic targets for patients with obstructive airways diseases. Novel therapies have the potential to substantially decrease the morbidity, mortality, and the financial burden related to these diseases.