Molecular Mechanisms of Pulmonary Hypertension in COPD

描述(由申请人提供)： 肺动脉高压(PH)是一种威胁生命的疾病，可与许多疾病一起发生，包括慢性阻塞性肺疾病(COPD)和特发性肺纤维化(IPF)。孤立地发生的、具有特征的肺肌小动脉重构的PH被归类为肺动脉高压(PAH)。导致PH的机械途径还知之甚少。我们对18名PAH患者、8名继发于IPF的PH患者和13名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，我们已经确定了与正常对照相比，继发于IPF的PAH和PH中的几个生物通路受到干扰。COPD继发PH的机制尚不清楚。还没有进行系统的全基因组研究来确定继发于COPD的PH中的所有生物学途径，并确定这些途径是否与其他形式的PH相同。这项建议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所特有的，还是与继发于IPF的PAH和PH共同的。我们建议研究来自肺组织研究联盟(LTRC)的肺组织样本，这些样本来自(1)COPD受试者和30%预测和血浆BNP&gt；40pg/ml(与继发性PH相关)和(2)COPD受试者和DLCO&gt；70%预测和血浆BNP&lt；30pg/ml(与正常肺动脉压相关)。我们假设，对来自LTRC的两个COPD队列(有无PH)和我们之前描述的队列(PAH、继发于IPF的PH和正常对照)的比较全基因组RNA表达分析将识别所有形式的PH共同的生物途径和每种潜在疾病的其他特有的生物学途径。因此，这项建议的具体目标是：1.获取并比较以下队列的肺组织中的RNA表达谱：a.来自LTRC的COPD和继发性PH(30%的预测和血浆BNP&GT；40pg/ml)；b.来自匹兹堡大学的PAH；c.来自匹兹堡大学的IPF；d.来自匹兹堡大学的正常对照组；e.COPD和来自LTRC的正常PAP(DLCO和GT；70%的预测和血浆BNP&gt；30pg/ml)。2.利用免疫印迹、肺组织蛋白芯片和免疫荧光技术，在蛋白质水平上确认在特定目的1下确定的关键生物通路的变化。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，也可与其他肺部疾病一起发生，包括慢性阻塞性肺疾病(COPD)和特发性肺纤维化(IPF)。即使有最好的治疗，只有大约一半的患者在确诊后存活五年。这个项目将分析基因在他们肺部的表达方式，以确定这种疾病是如何发展的，并确定治疗它的方法。(摘要结束)

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)