Airborne particulates exacerbate vascular remodeling in pulmonary hypertension - Pulmonary hypertension (PH) is an enigmatic and highly morbid condition with no available treatments for the most common forms of disease. Across the spectrum of PH, neither genetics nor the severity of primary disease fully explains the penetrance or extent of PH – hence, the identification of disease modifiers and their mechanisms of action is crucial both to understanding the disease and designing novel treatment modalities. In our preliminary work, we have identified epidemiological associations between ambient particulate matter (PM) and PH onset and mortality. However, the role of inhaled particulates in pulmonary vascular disease has never been fully investigated. Moreover, the diverse sources and compositions of respiratory exposures mandates that its effects be studied at the molecular level. In preliminary data, we observed an association between aryl hydrocarbon receptor (AHR) agonism in the plasma of PH patients with their residential PM2.5 exposures at the time of blood draw. In tandem, we have shown that PM causes inflammatory reprogramming in primary human pulmonary artery endothelial cells (HPAECs) through the upregulation of the AHR target gene Cytochrome P450 Family 1 Subfamily A Member 1 (CYP1A1); these pathways are similarly dysregulated in lung homogenate from rats exposed to orotracheal PM, who show evidence of pulmonary vascular remodeling in response to PM. Based on these data, we hypothesize that inhaled PM exacerbates pulmonary vascular remodeling by CYP1A1- dependent inflammation. To test this hypothesis, we propose 3 specific aims: Aim 1 will define population-level associations between AHR agonism, plasma metabolites, and the severity of PH; Aim 2 will determine if PM causes pulmonary endothelial pathophenotypes in PH and whether these pathophenotypes depend on CYP1A1; and Aim 3 will determine if PM causes PH in vivo and whether preclinical PH can be ameliorated by pharmacologic CYP1A1 inhibition. To facilitate my accomplishment of these aims and my transition to independence, I propose an educational program which will build upon my formal training in basic science in order to develop additional expertise in (1) environmental epidemiology, (2) computational analysis of large clinical datasets, (3) the use, analysis, and interpretation of metabolomic data. This scientific and educational program, combined with the support of my mentors and collaborators at the University of Pittsburgh, will assure my successful maturation into an independent translational physician-scientist. By these means, I will be ideally positioned for a career of impactful discoveries devoted to the treatment of PH.
