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Pre-clinical animal models of PAH

PAH临床前动物模型

基本信息

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
项目类别：
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

项目摘要

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