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.
The Preclinical Assessment Core will provide novel, comprehensive assessment of animal models of pulmonary hypertension that are essential for TPPG projects and investigators. The Core will assist in the implementation of rodent pulmonary hypertension animal models, and will perform complete hemodynamic assessments of pulmonary hypertension and heart function for mechanistic and therapeutic studies. In addition, the Core will perform imaging-based studies for evaluation of pulmonary vascular remodeling and will provide a Biobank of biological samples from a unique non-human primate model of pulmonary arterial hypertension secondary to humanized simian immunodeficiency virus infection (SIV-PAH), established and hemodynamically characterized in the previous funding cycle of the TPPG. The Preclinical Core will synergize with all the projects of the Program and the Clinical Core to serve as an integrated resource for validation of pulmonary hypertension target molecules as well as mechanistic pathways. These exceptional resources are essential for the Program and will be used by all TPPG investigators.
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