Integration of transcriptosome and microRNome in Understanding COPD Phenotypes

描述（由申请人提供）： COPD是美国第四大死亡原因，影响超过1600万人。这一疾病正在达到世界范围流行病的程度，其发病率正在上升，特别是在妇女中。在美国，超过85%的COPD是由于吸烟，近四分之一的美国人继续吸烟。COPD是一种异质性疾病，定义为不完全可逆的气流阻塞，不同的表型导致疾病的严重程度。基因组学和蛋白质组学研究均证实，COPD是一种复杂的异质性疾病，可能涉及炎症级联反应、蛋白水解凋亡途径以及其他尚未确定的途径的改变。微小RNA（microRNAs，miRNAs）是一类内源性小分子非编码RNA（长度约21-25 nt），存在于动物、植物和病毒等多种生物体中。miRNAs代表了一个新发现的基因调控层，通过靶向mRNA降解或抑制翻译。该研究的主要目的是确定明确定义的COPD患者队列肺组织中microRNA（miRNA）表达的不同模式，并将miRNA整合到定义COPD表型生物网络的系统方法中。具体目的1：将一组充分表征的COPD患者（GOLD 0-4）的肺组织miRNA/mRNA谱与疾病表型相关联。具体目标2：进行与疾病表型相关的特定miRNA的体外分析。(End摘要） 公共卫生相关性： COPD（慢性阻塞性疾病）是一种肺部疾病，每年影响数百万人，其特征是进行性、部分不可逆的气流限制。吸烟被认为是COPD发展的主要风险因素，然而，只有一小部分吸烟者（15-20%）曾经发展出具有临床意义的COPD。这突出了遗传易感性和其他环境因素作为疾病关键因素的重要性。我们建议采用多平台方法，整合microRNA和mRNA表达模式，以研究COPD疾病的明确临床表型。

DESCRIPTION (provided by applicant): COPD is the fourth leading cause of death in the United States, affecting over 16 million people. This disease is reaching worldwide epidemic proportions and its incidence is rising, particularly in women. More than 85% of COPD in the United States is due to smoking tobacco, and nearly one-quarter of Americans continue to smoke. COPD is a heterogeneous disease defined as airflow obstruction that is not fully reversible and different phenotypes contribute to the severity of the disease. Both genomic and proteomic studies have confirmed that COPD represents a complex and heterogeneous disease that likely involves alterations in the inflammatory cascade, proteolysis apoptotic pathways as well others that have yet to be identified. MicroRNAs (miRNAs) are a family of endogenous, small non-coding RNAs (approximately 21-25 nt long) expressed in many organisms including animals, plants, and viruses. MiRNAs represent a newly discovered layer of gene regulation by targeting mRNA for degradation or inhibition of translation. The primary goals of the proposed study are to identify distinct patterns of microRNA (miRNA) expression in the lung tissue of a well defined cohort of patients with COPD and integrate miRNAs into a systematic approach that defines biological networks across COPD phenotypes. Specific Aim 1: To correlate lung tissue miRNA/mRNA profiling in a cohort of well characterized COPD patients (GOLD 0-4) with disease phenotype. Specific Aim 2: Conduct in vitro analysis of specific miRNAs that correlate with disease phenotype. (End of Abstract) PUBLIC HEALTH RELEVANCE: Project Narrative COPD (Chronic Obstructive Disease) is a lung disease that affects millions of individuals per year and is characterized by progressive, partially irreversible airflow limitation. Tobacco smoke is considered the major risk factor for the development of COPD, however, only a small percentage of smokers (15-20%) ever develop clinically significant COPD. This highlights the importance of genetic susceptibility and other environmental factors as key contributors to disease. We propose to take a multiplatform approach that integrates both microRNA and mRNA expression patterns to study well defined clinical phenotypes of disease in COPD.