Pre-clinical animal models of PAH

PAH临床前动物模型

• 批准号: 7982560
• 负责人: Karen A Norris
• 金额: $ 49.3万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7982560
• 关键词: Angiography; Animal Model; Animals; Biological; Blood Vessels; Cardiac; Cardiac Catheterization Procedures; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Clinical Research; Clinical Trials; Complement; Complex; Coupled; Data; Development; Disease; Disease Progression; Disease model; Environment; Equipment; Evaluation; Exercise; Failure; Frequencies; Functional disorder; Gene Expression; Genetic; Goals; HIV; HIV Infections; Human; Hyperplasia; Hypoxemia; Hypoxia; Infection; Investigation; Lead; Link; Longitudinal Studies; Lung; Lung diseases; Macaca; Modeling; Molecular; Monkeys; Monocrotaline; Mus; Nitric Oxide; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Phase; Physiologic intraventricular pressure; Physiological; Positioning Attribute; Positron-Emission Tomography; Pre-Clinical Model; Primates; Process; Pulmonary Emphysema; Pulmonary Hypertension; Pulmonary Pathology; Pulmonary artery structure; Rattus; Reactive Oxygen Species; Recording of previous events; Research; Research Personnel; Right Ventricular Function; Right Ventricular Hypertrophy; Risk; Rodent Model; Role; SIV; Safety; Secondary to; Signal Pathway; Smoke; Stimulus; Therapeutic; Time; Translating; Universities; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular remodeling; Ventricular; Ventricular Remodeling; Virus Diseases; X-Ray Computed Tomography; base; bench to bedside; cigarette smoking; clinical application; design; drug development; efficacy evaluation; experience; genetic association; hemodynamics; indexing; insight; mouse model; nonhuman primate; novel; pre-clinical; preclinical study; pulmonary arterial hypertension; simian human immunodeficiency virus; small molecule; tissue fixing

Core B: Pre Clinical Animal Models of PAH The overall goals of the Pre-clinical Core are to provide expertise and novel assessments of pulmonary hypertension and right ventricular function in animal models that support TPPG projects and investigators. The Core will be directed by Dr. Karen Norris, who will lead the development of the non-human primate model of PAH and evaluation of candidate molecules developed in Projects 2 and 3. Dr. Hunter Champion will lead studies involving assessment of PAH in established rodent models utilized in Projects all Projects. The development of a novel, non-human primate model of PH, coupled with the extensive expertise in established mouse and rat models will provide a comprehensive evaluation of mechanistic pathways associated with disease progression. In addition, these models will be utilized by all Projects to evaluate genetic and environmental differences, as well as the effect of candidate small molecules on the progression of PH. Goals of the Core will be accomplished through the following SPECIFIC AIMS: Aim 1 will provide expertise and novel assessments of pulmonary hypertension and right ventricular function in mouse and rat models of pulmonary hypertension. Model assessments include micro-right heart catheterization, miliar assessments of right ventricular pressure and volume loops, Fulton-index, and exercise capacity. Validated available models include the hypoxia-exposed mouse, the VEGF inhibition mouse model, the monocrotyline exposed rat and mouse, the pulmonary artery banded mouse, and the smoked emphysema mouse with pulmonary hypertension. In Aim 2 we will further develop and characterize a primate model of pulmonary hypertension secondary to humanized simian immunodeficiency virus infection. The model will be characterized with CT-angiograms, PET/CT, right heart catheterization with assessments of pulmonary artery stiffness and RV pressure-volume function, RV and pulmonary pathology, and molecular characterization of pulmonary vasculature and RV by gene expression analysis. These studies will establish a non-human primate model of HIV- PAH and identify important correlates of disease progression. Aim 3 will provide a primate model in years 3-10 for pre-clinical trials of candidate small molecule drugs arising from Projects 2 and 3, that require additional safety evaluations prior to phase l-lb human clinical trials

核心B：PAH临床前动物模型 临床前核心的总体目标是提供肺部疾病的专业知识和新颖的评估 支持 TPPG 项目和研究人员的动物模型中的高血压和右心室功能。 核心项目将由凯伦·诺里斯 (Karen Norris) 博士领导，她将领导非人类灵长类动物的开发 PAH 模型以及项目 2 和 3 中开发的候选分子的评估。 Hunter Champion 博士 将领导涉及对项目所有项目中使用的已建立啮齿动物模型进行多环芳烃评估的研究。 开发一种新颖的非人类灵长类动物 PH 模型，并结合广泛的专业知识 建立的小鼠和大鼠模型将提供对机制途径的全面评估 与疾病进展有关。此外，所有项目都将利用这些模型来评估 遗传和环境差异，以及候选小分子对进展的影响 PH值。核心目标将通过以下具体目标来实现： 目标 1 将提供 小鼠和大鼠肺动脉高压和右心室功能的专业知识和新颖评估 肺动脉高压模型。模型评估包括微右心导管插入术、miliar 右心室压力和容量环、富尔顿指数和运动能力的评估。已验证 可用的模型包括缺氧小鼠、VEGF抑制小鼠模型、野百合替林模型 暴露的大鼠和小鼠、肺动脉带状小鼠和熏制肺气肿小鼠 肺动脉高压。在目标 2 中，我们将进一步开发和表征灵长类动物肺模型 人源化猿猴免疫缺陷病毒感染继发的高血压。该模型将是 以 CT 血管造影、PET/CT、右心导管插入术以及肺功能评估为特征 动脉僵硬度和右心室压力-容量函数、右心室和肺部病理学以及分子 通过基因表达分析表征肺血管系统和 RV。这些研究将建立 HIV-PAH 的非人类灵长类动物模型，并确定疾病进展的重要相关因素。目标3将 在 3-10 年提供灵长类动物模型，用于候选小分子药物的临床前试验 项目 2 和 3，需要在 l-lb 期人体临床试验之前进行额外的安全性评估