Integration of transcriptosome and microRNome in Understanding COPD Phenotypes

描述(由申请人提供)： 慢性阻塞性肺病是美国第四大死因，影响着1600多万人。这种疾病正在世界范围内流行，其发病率正在上升，特别是在妇女中。在美国，超过85%的慢性阻塞性肺病是由吸烟引起的，近四分之一的美国人继续吸烟。COPD是一种异质性疾病，定义为气流阻塞，不完全可逆，不同的表型导致疾病的严重程度。基因组和蛋白质组学研究证实，COPD是一种复杂的异质性疾病，可能涉及炎症级联反应、蛋白降解和凋亡途径的改变，以及其他尚未确定的疾病。MicroRNAs(MiRNAs)是一个内源性非编码小RNA家族(约21-25个核苷酸)，在包括动物、植物和病毒在内的许多生物中表达。MiRNAs代表了新发现的一层基因调节层，它通过靶向mRNA来降解或抑制翻译。这项拟议研究的主要目标是确定一组明确的COPD患者肺组织中microRNA(MiRNA)表达的不同模式，并将miRNAs整合到一种系统的方法中，该方法定义了跨COPD表型的生物网络。具体目标1：将一组特征良好的COPD患者(GOLD 0-4)的肺组织miRNA/mRNA图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miRNAs的体外分析。(摘要结束) 公共卫生相关性： 项目简介COPD(慢性阻塞性疾病)是一种每年影响数百万人的肺部疾病，其特征是进行性的、部分不可逆的气流受限。吸烟被认为是慢性阻塞性肺疾病发展的主要危险因素，然而，只有一小部分吸烟者(15%-20%)曾患上具有临床意义的慢性阻塞性肺疾病。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的方法，整合microRNA和mRNA的表达模式来研究COPD疾病明确的临床表型。

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.