Vascular Subphenotypes of Lung Disease

描述（由申请人提供）： 在这个项目中，我们提出了一个个性化的医学方法来研究晚期肺部疾病。我们假设常见疾病的亚表型，包括肺动脉高压（PAH），对治疗结果和反应性有深远的影响。该项目的总体目标是在主要肺部和全身性疾病（如COPD和HIV）的背景下定义PAH的常见机制和治疗途径。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translatlonal研究，解决PAH和晚期肺部疾病领域的主要当前和高影响问题。由于转化医学需要一种从实验室到床边到实验室的综合方法，我们从三个物种的临床前模型中开发了一个完整的转化克隆连续体，包括一种新型灵长类动物PAH模型、筛选和临床药物开发项目、人类血流动力学表型评估、遗传学和临床流行病学试验，最初集中在两个主要疾病靶点，COPD和HIV，其代表肺动脉高压亚表型的两种原型模型。我们提出的三个项目和核心都单独和合作地在这个翻译谱上对齐，推动努力了解疾病的基本机制，鉴定小分子治疗剂，开发肺部疾病血管亚表型的筛选生物标志物，并为II期和III期临床试验奠定基础。该项目前五年的成功有望在第6至10年发展到II-III期临床试验，并扩展到其他晚期肺部疾病，如间质性肺病和阻塞性睡眠呼吸暂停。 项目1：COPD患者的肺动脉高压：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：肺血管靶向NO治疗策略 核心A：行政核心 核心B：PAH临床前模型 核心C：转化血管表型组学、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