INTEGRATIVE GENOMICS AND THE FETAL ORIGINS OF IMPAIRED LUNG FUNCTION

描述(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。肺功能是生存的独立预测因素，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，肺功能的测量遵循类似的百分位数曲线，这表明肺发育和宫内暴露的遗传编程是以后生命中肺功能的关键决定因素。新疗法的开发需要一个全面的可改变的遗传靶点和分子途径的目录，这些基因靶点和分子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。综合基因组学寻求将基因数据与基因表达数据相结合，以更快地识别对基因功能有贡献的基因座。该项目的首要前提是培训主要研究人员将基因表达与人类早期肺发育的基因数据相结合，以确定关键的发育调节变量和有助于哮喘和COPD肺功能受损的发生和发展的生物途径。我们已经概述了一系列课程，这些课程将允许主要研究人员将综合基因组方法应用于人类胚胎肺发育。该项目的成功将促进主要研究人员向呼吸基因组学独立研究的过渡。此外，该项目的结果可能导致为阻塞性呼吸道疾病患者开发新的治疗方法。 公共卫生相关性：慢性阻塞性呼吸道疾病，包括哮喘和慢性阻塞性肺疾病(COPD)，是导致发病率和死亡率的主要原因之一，仅在美国就导致每年超过450亿美元的医疗费用。更好地了解影响肺功能损害的生物通路可能会为阻塞性呼吸道疾病患者确定创新的治疗靶点。新的治疗方法有可能大幅降低与这些疾病相关的发病率、死亡率和经济负担。

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.