To address our overall hypotheses that Pulmonary vascular disease/pulmonary hypertension (PHTN) is an important component of the COPD syndrome with distinct genetic and environmental determinants, we will 1. Identify genes responsible for cigarette smoke related PHTN using a mouse model and by exposing 36 strains of mice to long-term cigarette smoke and quantifying the PHTN phenotype in each strain. Given the dense SNP map, we will perform in silico mapping to identify specific genes responsible for the phenotype. We will also perform classic QTL crosses and use bioinformatics to identify the genes. 2. We have identified high fat diet as an important environmental factor that we hypothesize aggravates cigarette smoke related PHTN. We hypothesize that the mechanism for this synergistic effect of high fat is that both high fat and smoke cause ER stress and endothelial dysfunction, interfering with NO production. Low NO + the saturated fat excess will interfere with NO-mediated nitration of the polyunsaturated fatty acid, linoleic acid (LN02), highest affinity endogenous PPARy agonist known. Impaired PPARy signaling then leads to vascular PDGF-mediated smooth muscle cell proliferation and PHTN. We will both dissect this pathway and treat mice with exogenous PPARy agonists, thiazolidinedioines (TZDs). 3. To prepare for translation in years 6- 10 we will assess vascular disease by chest CT scans in a cohort of well-characterized patients with a spectrum of airflow obstruction and emphysema. We will derive and correlate indices of pulmonary vascular disease with physiology, patient symptoms, exercise performance and biomarkers of vascular disease. In addition to anatomic parameters, CT scan data will be used in conjunction with computational fluid dynamic tools to create personalized functional models of the pulmonary circulation. With the Clinical Core, we will also recruit a cohort of patients with COPD who will undergo right heart catheterizations (along with PFTs, echocardiography, exercise testing and chest CT) both to validate our findings and to test the hypothesis that vascular characteristics extracted from chest CT scan will correlate with pulmonary hypertension and pulmonary vascular responsiveness.

Public Health Relevance

In this project we will assess the overall hypotheses that 1. Pulmonary vascular disease/pulmonary hypertension (PHTN) is an important component of the COPD syndrome that has distinct genetic and environmental determinants and has an independent effect on symptoms and natural history, and 2. Molecular mechanisms identified in mice, are relevant to humans, and there are overiapping mechanisms involved in primary and secondary pulmonary hypertension, including COPD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL103455-01
Application #
7982556
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
$611,872
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

Showing the most recent 10 out of 162 publications