Systems Biology of Airway Disease

呼吸道疾病的系统生物学-项目 计划项目摘要 哮喘和慢性阻塞性肺疾病(COPD)是最常见的慢性疾病 阿龙。哮喘影响着1700万美国儿童和成人，仍然是发病的主要原因(一半 每年有100万人住院)，是造成学校和工作日损失的最常见原因。一千五百万 美国成年人被诊断为慢性阻塞性肺病；据估计，还有1200万人患有气流阻塞，但 都没有诊断出来。哮喘导致每年与哮喘相关的成本估计超过127亿美元。慢性阻塞性肺病是 在美国排名第三的死亡原因估计每年造成的损失高达499亿美元。综合健康 这些疾病的护理费用每年约为630亿美元。系统生物学与整合的遗传， 基因组和表观基因组学方法为阐明这些疾病的分子病因提供了 承诺为其预测、预防和更有效的治疗提供新的途径，因此， 最终降低医疗保健成本。我们继续寻求寻找共同的基因组决定因素 与人类疾病相关的哮喘和慢性阻塞性肺疾病及其在人体细胞中的功能影响 模特们。我们的研究战略是将基因数据(项目1)与转录数据(项目1)相结合 2)和甲基化/微RNA数据(项目3)使用系统基因组学方法 项目和基因组元素内部和之间的上位性相互作用，因此，重点是 用于分子验证和最终验证的功能最相关的路径和网络子模块 疾病洞察。在这项工作中，我们利用人类遗传学的重大进展，如HapMap项目， 提供对基因组的基本理解的Encode计划和人类表观基因组计划 复杂性告诉我们总体的具体目标：(1)整合遗传(SNP)、基因表达(转录) 以及这些疾病中哮喘、COPD和肺功能减退的表观遗传学(甲基化)数据；(2)建立模型 这些基因组数据源内部和之间的上位性交互作用，以定义关键的网络子模块 用于哮喘、COPD和肺功能减退的重叠；以及(3)从功能上验证这些网络 目标2中在分子水平上确定的子模块。为了实现这些目标，我们组建了一个 一群在一起工作了15年以上的有成就的研究人员，他们是人类方面的专家 遗传学、基因表达和综合基因组学、表观遗传学、系统生物学、基因组统计学和 生物信息学和功能基因组学。这组调查人员发表了500多篇同行评议 2007年以来的原始手稿和123份发表的科学报告(另有以下两种情况下的手稿 与本申请的主题直接相关的文件(正在修订或等待决定)。

SYSTEMS BIOLOGY OF AIRWAYS DISEASE – PROGRAM PROJECT PROGRAM PROJECT ABSTRACT Asthma and chronic obstructive pulmonary disease (COPD), are the most common chronic diseases of the lung. Asthma affects 17 million U.S. children and adults and remains a major cause of morbidity (one-half million hospitalizations a year), and is the most common cause of school and work days lost. Fifteen million U.S. adults carry a diagnosis of COPD; it is estimated that 12 million more people have airflow obstruction but are undiagnosed. Asthma results in an estimated yearly asthma-related cost of over $12.7 billion. COPD is the third leading cause of mortality in the U.S. with an estimated annual cost of $49.9 billion. The combined health care costs for these conditions approximate $63 billion per year. Systems biology with integrative genetic, genomic and epigenomic approaches to elucidate the molecular causes of these diseases offer the promise of providing new avenues for their prediction, prevention and more effective treatment, thus, ultimately reducing health care costs. We continue to seek to find common genomic determinants for asthma and COPD relevant to human disease and assess their functional effects in human cellular models. Our research strategy is to integrate genetic data (Project 1) with transcriptomic data (Project 2) and methylation/microRNA data (Project 3) using systems genomics approaches that exploit epistatic interaction both within and between the projects and genome elements and, thus, focuses on the functionally most relevant pathways and network submodules for molecular validation and ultimate disease insights. In this effort, we leverage major advances in human genetics such as the HapMap Project, the ENCODE Project and the Human Epigenome Project that provide the basic understanding of genome complexity that informs our overall specific aims: (1) to integrate genetic (SNP), gene expression (transcript) and epigenetic (methylation) data for asthma, COPD and reduced lung function in these disorders; (2) to model the epistatic interactions within and between these genomic data sources to define critical network submodules for the overlap of asthma, COPD and reduced lung function; and (3) to functionally validate these network submodules identified in Aim 2 at the molecular level. To accomplish these aims we have assembled an accomplished group of investigators who have worked together for over 15 years and are experts in human genetics, gene expression and integrative genomics, epigenetics, systems biology, genomic statistics and bioinformatics and functional genomics. This group of investigators has published over 500 peer-reviewed original manuscripts since 2007 and 123 published scientific reports (with additional manuscripts either under development, under revision or awaiting decisions) directly related to the topic of the present application.