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

Public Health Relevance

The Pre-clinical Core will provide comprehensive expertise and novel assessments of PAH in pre-clinical models. Additionally, these studies will advance the field with the development and characterization of a novel, non-human primate model of PAH. This new model will complement the advanced physiological and molecular characterization of our existing rodent models and will provide a much needed intermediate step between drug development and clinical application

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL103455-01
Application #
7982560
Study Section
Special Emphasis Panel (ZHL1-CSR-A (M1))
Project Start
2011-06-01
Project End
2016-04-30
Budget Start
2011-06-01
Budget End
2012-04-30
Support Year
1
Fiscal Year
2011
Total Cost
$493,017
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kim-Campbell, Nahmah; Gretchen, Catherine; Callaway, Clifton et al. (2017) Cell-Free Plasma Hemoglobin and Male Gender Are Risk Factors for Acute Kidney Injury in Low Risk Children Undergoing Cardiopulmonary Bypass. Crit Care Med 45:e1123-e1130
Meng, Qingqing; Lai, Yen-Chun; Kelly, Neil J et al. (2017) Development of a Mouse Model of Metabolic Syndrome, Pulmonary Hypertension, and Heart Failure with Preserved Ejection Fraction. Am J Respir Cell Mol Biol 56:497-505
Meijles, Daniel N; Sahoo, Sanghamitra; Al Ghouleh, Imad et al. (2017) The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1. Sci Signal 10:
Hughan, Kara S; Wendell, Stacy Gelhaus; Delmastro-Greenwood, Meghan et al. (2017) Conjugated Linoleic Acid Modulates Clinical Responses to Oral Nitrite and Nitrate. Hypertension :
Gladwin, Mark T (2017) Translational Advances in the Field of Pulmonary Hypertension Bench to Bedside: How Fundamental Discoveries in Science Are Advancing Our Understanding and Therapy of Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 195:1-3
Fazzari, Marco; Khoo, Nicholas K H; Woodcock, Steven R et al. (2017) Nitro-fatty acid pharmacokinetics in the adipose tissue compartment. J Lipid Res 58:375-385
Grzegorzewska, Agnieszka P; Seta, Francesca; Han, Rong et al. (2017) Dimethyl Fumarate ameliorates pulmonary arterial hypertension and lung fibrosis by targeting multiple pathways. Sci Rep 7:41605
Kelly, Neil J; Radder, Josiah E; Baust, Jeffrey J et al. (2017) Mouse Genome-Wide Association Study of Preclinical Group II Pulmonary Hypertension Identifies Epidermal Growth Factor Receptor. Am J Respir Cell Mol Biol 56:488-496
Radder, Josiah E; Zhang, Yingze; Gregory, Alyssa D et al. (2017) Extreme Trait Whole-Genome Sequencing Identifies PTPRO as a Novel Candidate Gene in Emphysema with Severe Airflow Obstruction. Am J Respir Crit Care Med 196:159-171
Pena, Andressa; Kobir, Ahasanul; Goncharov, Dmitry et al. (2017) Pharmacological Inhibition of mTOR Kinase Reverses Right Ventricle Remodeling and Improves Right Ventricle Structure and Function in Rats. Am J Respir Cell Mol Biol 57:615-625

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