Pulmonary hypertension in COPD: genetic and enviormental determinants

为了解决我们关于肺血管疾病/肺动脉高压(PHTN)是一种 COPD综合征的重要组成部分与不同的遗传和环境决定因素，我们将1。 使用小鼠模型和暴露36个基因来识别与吸烟相关的PHTN的基因 对长期吸烟的小鼠品系的PHTN表型进行量化。给定 致密的SNP图谱，我们将进行电子作图以确定与表型相关的特定基因。 我们还将进行经典的QTL杂交，并使用生物信息学来识别基因。2.我们已确定 高脂肪饮食是一个重要的环境因素，我们假设与加重香烟烟雾有关 PHTN.我们假设，高脂肪的这种协同作用的机制是高脂肪和 吸烟导致内质网应激和内皮功能障碍，干扰一氧化氮的产生。低NO+饱和 脂肪过量会干扰NO介导的多不饱和脂肪酸亚油酸(LN02)的硝化， 已知的最高亲和力内源性PPARy激动剂。PPARy信号受损导致血管 PDGF介导的血管平滑肌细胞增殖和PHTN。我们都会解剖这条路径并治疗 使用外源性PPARy激动剂的小鼠，噻唑烷二核苷酸(TZDS)。3.为6年内的翻译工作做准备- 我们将通过胸部CT扫描来评估一组具有良好特征的血管疾病患者。 气流阻塞和肺气肿的谱系。我们将推导和关联肺血管指数 疾病与生理、患者症状、运动能力和血管疾病的生物标志物有关。在……里面 除了解剖参数，CT扫描数据还将与计算流体力学结合使用 创建个性化的肺循环功能模型的工具。有了临床核心，我们将 还招募了一组COPD患者，他们将接受右心导管术(连同PFT， 超声心动图、运动试验和胸部CT)，以验证我们的发现并检验以下假设 从胸部CT扫描提取的血管特征将与肺动脉高压和 肺血管反应性。

To address our overall hypotheses that Pulmonary vascular disease/pulmonary hypertension (PHTN) is an important component of the COPD syndrome with distinct genetic and environmental determinants, we will 1. Identify genes responsible for cigarette smoke related PHTN using a mouse model and by exposing 36 strains of mice to long-term cigarette smoke and quantifying the PHTN phenotype in each strain. Given the dense SNP map, we will perform in silico mapping to identify specific genes responsible for the phenotype. We will also perform classic QTL crosses and use bioinformatics to identify the genes. 2. We have identified high fat diet as an important environmental factor that we hypothesize aggravates cigarette smoke related PHTN. We hypothesize that the mechanism for this synergistic effect of high fat is that both high fat and smoke cause ER stress and endothelial dysfunction, interfering with NO production. Low NO + the saturated fat excess will interfere with NO-mediated nitration of the polyunsaturated fatty acid, linoleic acid (LN02), highest affinity endogenous PPARy agonist known. Impaired PPARy signaling then leads to vascular PDGF-mediated smooth muscle cell proliferation and PHTN. We will both dissect this pathway and treat mice with exogenous PPARy agonists, thiazolidinedioines (TZDs). 3. To prepare for translation in years 6- 10 we will assess vascular disease by chest CT scans in a cohort of well-characterized patients with a spectrum of airflow obstruction and emphysema. We will derive and correlate indices of pulmonary vascular disease with physiology, patient symptoms, exercise performance and biomarkers of vascular disease. In addition to anatomic parameters, CT scan data will be used in conjunction with computational fluid dynamic tools to create personalized functional models of the pulmonary circulation. With the Clinical Core, we will also recruit a cohort of patients with COPD who will undergo right heart catheterizations (along with PFTs, echocardiography, exercise testing and chest CT) both to validate our findings and to test the hypothesis that vascular characteristics extracted from chest CT scan will correlate with pulmonary hypertension and pulmonary vascular responsiveness.