Pulmonary hypertension in COPD: genetic and enviormental determinants

为了解决我们的总体假设，即肺血管疾病/肺动脉高压（PHTN）是一种 COPD综合征的重要组成部分，具有不同的遗传和环境决定因素，我们将1。 使用小鼠模型并通过暴露36个与香烟烟雾相关的PHTN相关的基因， 小鼠品系长期吸烟，并定量每个品系中的PHTN表型。鉴于 为了构建高密度SNP图谱，我们将进行计算机作图，以确定负责表型的特定基因。 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.我们已经确定 高脂肪饮食作为一个重要的环境因素，我们假设， PHTN。我们推测，高脂肪的这种协同效应的机制是高脂肪和 吸烟引起ER应激和内皮功能障碍，干扰NO产生。低NO +饱和 脂肪过量将干扰NO介导的多不饱和脂肪酸，亚油酸（LNO 2）， 已知最高亲和力的内源性PPARy激动剂。受损的PPARy信号传导然后导致血管 PDGF介导的平滑肌细胞增殖和PHTN。我们将解剖这条通路 用外源性PPARy激动剂噻唑烷二酮类（TZD）处理小鼠。3.准备在6年内翻译- 我们将通过胸部CT扫描对一组特征明确的患者进行血管疾病评估， 气流阻塞和肺气肿频谱。我们将推导并关联肺血管的指数 疾病与生理学、患者症状、运动表现和血管疾病的生物标志物。在 除了解剖参数，CT扫描数据将与计算流体动力学结合使用 创建个性化肺循环功能模型的工具。通过临床核心，我们将 还招募了将接受右心导管插入术（沿着PFT， 超声心动图、运动试验和胸部CT）来验证我们的发现，并检验假设， 从胸部CT扫描中提取的血管特征将与肺动脉高压相关， 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.