Vascular Subphenotypes of Lung Disease

描述(由申请人提供)： 在这个项目中，我们提出了一种个性化医学方法来研究晚期肺部疾病。我们假设，包括肺动脉高压(PAH)在内的常见疾病的亚型对结果和治疗反应有深远的影响。该计划的总体翻译目标是在COPD和HIV等主要肺部和全身疾病的背景下确定PAH的共同机制和治疗途径。我们提出的三个主要项目和两个核心旨在整合和协同基础转克隆研究，以解决PAH和晚期肺部疾病领域当前的重大和高影响问题。由于转化医学需要一种从床到床的综合方法，我们从三个物种的临床前模型开发了一个完整的翻译克隆连续体，包括一个新的灵长类PAH模型、筛查和临床药物开发计划、人类血液动力学表型评估、遗传学和临床流行病学试验，最初集中在两个主要疾病靶标COPD和HIV上，这两个疾病代表了肺动脉高压亚型的两个原型模型。我们提出的三个项目和核心都单独和协作地在这一翻译谱上对齐，推动努力了解疾病的基本机制，识别小分子治疗剂，开发肺部疾病血管亚型的筛选生物标记物，并为第二阶段和第三阶段临床试验奠定基础。该项目头五年的成功预计将发展到11阶段临床试验，并在6至10年内推广到其他晚期肺部疾病，如间质性肺疾病和阻塞性睡眠呼吸暂停。 项目1：慢性阻塞性肺病的肺动脉高压：遗传和环境决定因素 项目2：肺血管疾病中的ROS信号和NOS解偶联 项目3：针对肺血管的NO治疗策略 核心A：行政核心 核心B：PAH的临床前模型 翻译血管表型组学、基因组学和流行病学核心

DESCRIPTION (provided by applicant): In this program project, we propose a Personalized Medicine approach to the study of advanced lung disease. We hypothesize that sub-phenotypes of common diseases, including pulmonary arterial hypertension (PAH), have a profound influence on outcome and responsiveness to therapy. The overarching translatlonal goal of this program is to define common mechanistic and therapeutic pathways for PAH in the context of major lung and systemic diseases, such as COPD and HIV. Our proposed three major projects and two cores are designed to integrate and synergize fundamental translatlonal research addressing major current and high impact problems in the PAH and advanced lung disease field. Because translational medicine requires a bench-to-bedside-to-bench integrated approach, we developed a full translatlonal continuum from preclinical models in three species, including a novel primate PAH model, screening and clinical drug development programs, human hemodynamic phenomic assessments, genetics, and clinical epidemiological trials focused initially on two major disease targets, COPD and HIV, which represent two prototypic models of the pulmonary hypertension sub-phenotype. Our three proposed projects and cores all individually and collaboratively align across this translational spectrum, driving an effort to understand fundamental mechanisms of disease, identify small molecule therapeutic agents, develop screening biomarkers for vascular sub-phenotypes of lung disease, and to set the stage for phase II and III clinical trials. Successes in the first five years of this project are expected to develop into phase ll-lll clinical trials and extension to other advanced lung diseases, such as interstitial lung disease and obstructive sleep apnea, in years 6 to 10. Project 1: Pulmonary hypertension in COPD: Genetic and Environmental Determinants Project 2: ROS signaling and NOS uncoupling in pulmonary vascular disease Project 3: Pulmonary vascular-targeted NO therapeutic strategies Core A: Administrative core Core B: Pre-Clinical Models of PAH Core C: Translational Vascular Phenomics, Genomics and Epidemiology Core