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疾病的专业知识和新的评估。 高血压和右心室功能的动物模型，支持TPPG项目和研究人员。 核心将由凯伦·诺里斯博士指导，她将领导非人类灵长类动物的开发。 PAH模型和项目2和3中开发的候选分子的评价。亨特·钱皮恩博士 将领导研究，包括在项目所有项目中使用的已建立的啮齿动物模型中评估PAH。 一种新型的非人灵长类PH模型的开发，加上广泛的专业知识， 已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，所有项目都将使用这些模型来评估 遗传和环境差异，以及候选小分子对进展的影响 核心目标将通过以下具体目标实现：目标1将提供 小鼠和大鼠肺动脉高压和右心室功能专业知识和新的评估方法 肺动脉高压模型。模型评估包括微型右心导管插入术、miliar 评估右心室压力和容积环、富尔顿指数和运动能力。验证 可用的模型包括缺氧暴露小鼠、VEGF抑制小鼠模型、久效霉素 暴露的大鼠和小鼠、肺动脉结扎小鼠和吸烟肺气肿小鼠， 肺动脉高压在目标2中，我们将进一步开发和表征肺结核的灵长类动物模型。 人源化猴免疫缺陷病毒感染继发高血压该车型将 通过CT血管造影、PET/CT、右心导管检查和肺功能评估进行表征 动脉僵硬度和RV压力-容量功能，RV和肺病理学，以及分子 通过基因表达分析表征肺血管和RV。这些研究将建立 一个非人类灵长类动物模型的HIV- PAH和确定重要的相关性疾病的进展。目标3将 在3-10年内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，在l-lb期人体临床试验之前需要进行额外的安全性评价