Molecular Mechanisms of Pulmonary Hypertension in COPD

描述（由申请人提供）： 肺动脉高压（PH）是一种危及生命的疾病，可能与许多疾病相关，包括慢性阻塞性肺疾病（COPD）和特发性肺纤维化（IPF）。孤立性肺动脉高压（PAH），伴有肺肌性小动脉的特征性重塑，被归类为肺动脉高压（PAH）。导致PH的机制途径知之甚少。我们对18例PAH受试者、8例继发于IPF的PH受试者和13例正常受试者的肺组织进行了全基因组RNA表达谱分析。通过这种方法，我们已经确定了相对于正常对照，继发于IPF的PAH和PH中受到干扰的几种生物学途径。 继发于COPD的PH机制尚不清楚。尚未进行系统的全基因组研究来确定继发于COPD的PH中受到干扰的所有生物学途径，并确定这些途径是否与其他形式的PH共同。本提案的总体目标是确定哪些遗传、分子和细胞机制是继发于COPD的PH特有的，或与PAH和继发于IPF的PH共有。我们建议研究来自肺组织研究联盟（LTRC）的肺组织标本，这些标本来自（1）患有COPD且DLCO < 30% of predicted and plasma BNP >40 pg/ml（与继发性PH相关）的受试者和（2）患有COPD且DLCO &gt; 70%预测值且血浆BNP &lt; 30 pg/ml（与正常肺动脉压[PAP]相关）的受试者。我们假设，对来自LTRC（伴和不伴PH）和我们先前表征的队列（PAH、继发于IPF的PH和正常对照）的两个COPD队列进行比较性全基因组RNA表达分析，将识别所有形式的PH共有的生物学途径和每种基础疾病特异性的其他生物学途径。因此，本提案的具体目标是：1.为了获得并比较来自以下群组的肺组织中的RNA表达谱：来自LTRC的COPD和继发性PH（DLCO < 30% of predicted and plasma BNP >40 pg/ml）; B.来自匹兹堡大学的PAH; c.来自匹兹堡大学的继发于IPF的PH; d.来自匹兹堡大学的正常对照; e.来自LTRC的COPD和正常PAP（DLCO &gt;预测值的70%且血浆BNP &lt; 30 pg/ml）。 2.使用免疫印迹、肺组织蛋白微阵列和免疫荧光法，在蛋白水平上确认特定目标1下确定的关键生物学途径的变化。 公共卫生相关性：肺动脉高压（PH）是一种危及生命的疾病，可单独发生或与其他肺部疾病（包括慢性阻塞性肺病（COPD）和特发性肺纤维化（IPF））相关。即使采用最好的治疗方法，也只有大约一半的患者在确诊后存活五年。该项目将分析基因在肺部的表达方式，以确定这种疾病是如何发展的，并确定治愈它的方法。

DESCRIPTION (provided by applicant): Pulmonary hypertension (PH) is a life-threatening condition which can occur in association with many diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). PH occurring in isolation, with characteristic remodeling of pulmonary muscular arterioles, is classified as pulmonary arterial hypertension (PAH). The mechanistic pathways leading to PH are poorly understood. We have performed genome-wide RNA expression profiling in lung tissue from 18 PAH subjects, 8 subjects with PH secondary to IPF, and 13 normal subjects. With this approach, we have identified several biological pathways that are perturbed in PAH and PH secondary to IPF relative to normal controls. The mechanisms of PH secondary to COPD remain unclear. No systematic genome-wide study has been performed to identify all biological pathways that are perturbed in PH secondary to COPD, and to determine whether these pathways are common to other forms of PH. The overall goal of this proposal is to determine which genetic, molecular, and cellular mechanisms are specific to PH secondary to COPD, or shared with PAH and PH secondary to IPF. We propose to study lung tissue specimens from the Lung Tissue Research Consortium (LTRC) from (1) subjects with COPD and a DLCO < 30% of predicted and plasma BNP > 40 pg/ml (associated with secondary PH) and (2) subjects with COPD and a DLCO > 70% of predicted and plasma BNP < 30 pg/ml (associated with normal pulmonary artery pressures [PAP]). We hypothesize that comparative genome-wide RNA expression analysis of two COPD cohorts from the LTRC (with and without PH) and our previously characterized cohorts (PAH, PH secondary to IPF, and normal controls) will identify both biological pathways common to all forms of PH and others specific to each underlying disease. Accordingly, the specific aims of this proposal are: 1. To acquire and to compare RNA expression profiles in lung tissue from the following cohorts: a. COPD and secondary PH (DLCO < 30% of predicted and plasma BNP > 40 pg/ml) from the LTRC; b. PAH from the University of Pittsburgh; c. PH secondary to IPF from the University of Pittsburgh; d. Normal controls from the University of Pittsburgh; e. COPD and normal PAP (DLCO > 70% of predicted and plasma BNP < 30 pg/ml) from the LTRC. 2. To confirm at the protein level changes in key biological pathways identified under Specific Aim 1 using immunoblots, lung tissue protein microarrays, and immunofluorescence. PUBLIC HEALTH RELEVANCE: Pulmonary hypertension (PH) is a life-threatening disease which can occur alone or in association with other lung diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Even with the best treatments, only about half of patients survive five years after diagnosis. This project will analyze the way genes are expressed in their lungs, to determine how this disease develops and to identify ways of curing it. (End of Abstract)