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.
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.
|Raghu, Vineet K; Ramsey, Joseph D; Morris, Alison et al. (2018) Comparison of strategies for scalable causal discovery of latent variable models from mixed data. Int J Data Sci Anal 6:33-45|
|Kudryashova, Tatiana V; Shen, Yuanjun; Pena, Andressa et al. (2018) Inhibitory Antibodies against Activin A and TGF-? Reduce Self-Supported, but Not Soluble Factors-Induced Growth of Human Pulmonary Arterial Vascular Smooth Muscle Cells in Pulmonary Arterial Hypertension. Int J Mol Sci 19:|
|Freeman, Bruce A; O'Donnell, Valerie B; Schopfer, Francisco J (2018) The discovery of nitro-fatty acids as products of metabolic and inflammatory reactions and mediators of adaptive cell signaling. Nitric Oxide 77:106-111|
|Villacorta, Luis; Minarrieta, Lucia; Salvatore, Sonia R et al. (2018) In situ generation, metabolism and immunomodulatory signaling actions of nitro-conjugated linoleic acid in a murine model of inflammation. Redox Biol 15:522-531|
|Remy, Kenneth E; Cortés-Puch, Irene; Solomon, Steven B et al. (2018) Haptoglobin improves shock, lung injury, and survival in canine pneumonia. JCI Insight 3:|
|Rom, Oren; Khoo, Nicholas K H; Chen, Y Eugene et al. (2018) Inflammatory signaling and metabolic regulation by nitro-fatty acids. Nitric Oxide :|
|D'Amore, Antonio; Fazzari, Marco; Jiang, Hong-Bin et al. (2018) Nitro-Oleic Acid (NO2-OA) Release Enhances Regional Angiogenesis in a Rat Abdominal Wall Defect Model. Tissue Eng Part A 24:889-904|
|Schopfer, Francisco J; Vitturi, Dario A; Jorkasky, Diane K et al. (2018) Nitro-fatty acids: New drug candidates for chronic inflammatory and fibrotic diseases. Nitric Oxide 79:31-37|
|Farkas, Daniela; Thompson, A A Roger; Bhagwani, Aneel R et al. (2018) Toll-like Receptor 3 is a Therapeutic Target for Pulmonary Hypertension. Am J Respir Crit Care Med :|
|Goncharov, Dmitry A; Goncharova, Elena A; Tofovic, Stevan P et al. (2018) Metformin Therapy for Pulmonary Hypertension Associated with Heart Failure with Preserved Ejection Fraction versus Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 198:681-684|
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