Preclinical Assessment Core

摘要：临床前评估核心将由三个部分组成：血液动力学亚核心、 成像亚核和存储从独特的非人类灵长类动物收集的生物样本的生物库 人源化猴免疫缺陷病毒感染继发肺动脉高压模型的建立 (小岛屿发展中国家--多环芳烃)在上一个项目方案方案的供资周期中建立并确定了其特点。所有三个组件都是 对于此tPPG应用程序的机械学和平移研究目标至关重要。 具体目标：临床前评估核心的具体目标是：1.提供新颖的专业知识 肺动脉高压小鼠和大鼠模型的血流动力学评价 肺动脉高压伴心力衰竭和保留射血分数(PH-HFpEF)。2.提供 在PAH和PH-HFpEF啮齿动物的机制和病理评估的影像研究方面的专长 模特们。3.建立SIV-PAH灵长类动物模型的生物库。 核心服务/研究计划：血液动力学分核心将协助实施 建立PAH和PH-HFpEF的啮齿动物模型，用彩色多普勒血流动力学评价双室血流动力学。 压力-容量测量和超声心动图测量用于无创性评价心脏 PAH和PH-HFpEF啮齿动物的结构和功能。成像组件将在以下方面提供专业知识 动物模型活体和固定标本组织的制备、储存和免疫标记。这些 将包括识别关键的信号通路以及疾病病理和进展的特征 通过图像分析方法定量测量肺血管和心脏重构。这个 CORE将提供对肺、心脏组织、肺动脉平滑肌细胞(PASMC)、 SIV-PAH灵长类动物模型不同时间点的血浆、支气管肺泡灌洗和粪便样本 这将使从疾病早期到晚期的功能相关性和机制研究成为可能。 PASMC将被用来开发一个体外模型来评估代谢紊乱的影响和治疗 PASMC扩散的候选者。 意义和协同作用：临床前核心将支持PAH和PH-HFpEF动物模型的研究 紧密地概括了人类疾病的发病机制和临床结果，更重要的是， 在评估新疗法方面证明了其价值。所有项目将使用临床前评估核心的资源来： 1)检验PAH和PH-HFpEF发病机制假说，2)检验新的 在已建立的PAH和PH-HFpEF啮齿动物模型中的治疗，以及3)评估 来自SIV-PAH模型的生物样本。此外，临床前核心将与存储库协同工作 来自临床核心中心的人体样本作为验证肺部疾病的综合资源 高血压靶分子和机制途径。

Summary: The Preclinical Assessment Core will be comprised of three components: a hemodynamic subcore, an imaging subcore, and a Biobank housing biological samples collected from an unique non-human primate model of pulmonary arterial hypertension secondary to humanized simian immunodeficiency virus infection (SIV-PAH) established and characterized in the previous funding cycle of the tPPG. All three components are essential for the mechanistic and translational research goals of this tPPG application. Specific Aims: The specific aims of the Preclinical Assessment Core are: 1.To provide expertise in novel hemodynamic assessments of pulmonary hypertension and cardiac function in mouse and rat models of PAH and pulmonary hypertension with heart failure and preserved ejection fraction (PH-HFpEF). 2. To provide expertise in imaging-based studies for mechanistic and pathologic assessment of PAH and PH-HFpEF rodent models. 3. To develop a Biobank from the primate model of SIV-PAH. Core Services/Research Plan: The Hemodynamic subcore will provide assistance in the implementation of rodent animal models of PAH and PH-HFpEF, biventricular hemodynamic assessment by Doppler flow and pressure-volume measurements, and echocardiographic measurements for non-invasive evaluation of cardiac structure and function in rodents with PAH and PH-HFpEF. The Imaging component will provide expertise in the preparation, storage and immuno-labeling of tissues in living and fixed samples from animal models. These will include identification of key signaling pathways and characterization of disease pathology and progression by quantitative measures of pulmonary vascular and heart remodeling using image analysis approaches. The Core will provide access to a Biobank of lung, heart tissue, pulmonary artery smooth muscle cells (PASMC), plasma, bronchoalveolar lavage, and fecal samples from different time points of the SIV-PAH primate model that will allow functional correlations and mechanistic studies from early to advanced stages of the disease. PASMC will be used to develop an in vitro model to evaluate the effect of metabolic disorders and therapeutic candidates in PASMC proliferation. Significance and synergy: The Preclinical core will support studies in animal models of PAH and PH-HFpEF that closely recapitulate the pathogenesis and clinical outcome of human disease, and more importantly, have proven value in evaluating new therapies. All Projects will use resources of the Preclinical Assessment Core to: 1) test mechanistic hypotheses of the pathogenesis of PAH and PH-HFpEF, 2) test the efficacy of new therapeutics in established rodent models of PAH and PH-HFpEF, and 3) evaluate molecular mechanisms in biological samples from the SIV-PAH model. In addition, the Preclinical Core will synergize with the repository of human samples from the Clinical Core to serve as an integrated resource for validation of pulmonary hypertension target molecules as well as mechanistic pathways.