Metabolomic Profiling of Explanted Pulmonary Arterial Hypertension Lungs

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 DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a lethal disease characterized by endothelial cell dysfunction and progressive inward vascular growth that leads to hypertension and ultimately right heart failure. Currently approved PAH therapies focus on dilating structurally-abnormal vessels for improved quality of life, however lung transplantation remains the only cure for advanced disease. PAH is associated with metabolic defects as patients demonstrate insulin resistance and impaired intracellular glucose metabolism. Here we seek to identify aberrant metabolic pathways associated with PAH as opportunities for therapeutic intervention, by profiling the metabolome of endothelial cells that have been implicated as the site of disease origin. In addition, we seek to understand whether an altered metabolome or post-translational modification status underlies the aberrant PPARγ-protein complexes associated with PAH. To investigate we will immunoprecipitate PPARγ from endothelial cells and apply metabolomic and proteomic analysis to identify bound small molecules and covalent protein modifications. Altered metabolites and aberrant metabolic pathways associated with PAH will be validated with chemical and genetic tools in cellular assays. The overarching goal of this proposal is to characterize the molecular underpinnings of PAH as a means to identify novel therapeutic strategies.