Pre-clinical animal models of PAH

核心B：PAH的临床前动物模型 临床前核心的总体目标是提供专业知识和新颖的肺病评估 支持TPPG项目和研究人员的动物模型中的高血压和右心功能。 核心将由Karen Norris博士执导，他将领导非人类灵长类动物的开发 项目2和项目3中开发的多环芳烃模型和候选分子的评估。 将领导在所有项目中使用的已建立的啮齿动物模型中评估多环芳烃的研究。 一种新的、非人类的灵长类动物模型的开发，加上在 已建立的小鼠和大鼠模型将提供对机械途径的全面评估 与疾病进展有关。此外，所有项目都将利用这些模型进行评估 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实现：目标1将提供 小鼠和大鼠肺动脉高压和右心功能的专业知识和新的评估方法 肺动脉高压模型。模型评估包括微创右心导管术， 右室压力和容量环、富尔顿指数和运动能力的评估。经过验证 可用的模型包括低氧暴露小鼠、血管内皮生长因子抑制小鼠模型、单核细胞色素 暴露的大鼠和小鼠，肺动脉结扎的小鼠，吸烟的肺气肿小鼠 肺动脉高压。在目标2中，我们将进一步发展和表征一种灵长类动物模型。 继发于人源化猴免疫缺陷病毒感染的高血压。模型将是 以CT血管造影、PET/CT、右心插管和肺功能评估为特征 动脉僵硬和右室压力-容量功能，右室和肺病理，以及分子 肺血管和RV基因表达分析的特征。这些研究将确定 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和项目3，需要在L-1b期人体临床试验之前进行额外的安全性评估

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