Genomics of Pulmonary Vascular Disease

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PROJECT SUMMARY Pulmonary hypertension (PH) is a potentially fatal disease characterized by progressive pulmonary vascular remodeling and elevated pulmonary artery pressure, leading to right heart failure. The molecular etiology is poorly understood, even in familial PH where mutations in the bone morphogenetic protein (BMP) signaling pathway are well characterized. Our approach focuses on understanding the germline genetic variation that predisposes to PH, and somatic changes within the lung that may contribute to the onset and/or progression of the disease. We were the first to identify chromosome abnormalities in pulmonary artery endothelial cells from explant PH lung tissue. Levels of DNA damage were higher in lung and blood cells from patients than controls, and correlated with the amount of reactive oxygen species. Similar changes were found in the blood of patients' relatives, suggesting this may be genetically determined. Our current studies utilize state of the art next generation sequencing approaches in lung tissues and cells to test the hypothesis that increased levels of DNA damage predispose to genetic alterations in the lung, and may contribute to vascular remodeling in PH. We are also testing novel therapeutic approaches to correct BMP signaling in familial PH and hereditary hemorrhagic telangiectasia (HHT), a related vascular disorder also caused by mutations in the BMP pathway. HHT carries high morbidity associated with risk of hemorrhage from arteriovenous malformations in the lungs, liver and brain. Our current studies focus on ataluren, a small molecule with orphan drug status that promotes ribosomal readthrough of nonsense mutations. In preliminary studies, BMP signaling was restored in cells from 5 of 6 patients with different nonsense mutations. In vitro studies in blood or lung-derived endothelial cells from affected patients are complimented with treatment and prevention studies in a genetic mouse model. This Outstanding Investigator Award proposal combines these two major themes into a unified research program in the genomics of pulmonary vascular disease. We will harness the emerging power of single cell sequencing technologies to develop novel analyses of endothelial cells that adhere to the Swan-Ganz catheter after routine cardiac catheterization. This will extend our current studies in several new directions: (1) enabling direct analysis of DNA damage markers in disease-relevant cells; (2) providing immediate ex vivo readouts of drug responses; (3) developing novel diagnostic and prognostic signatures; and (4) perhaps ultimately providing single cell resolution of the timing and evolution of somatic mutations in the PH lung. Through leadership in the genomics components of two NHLBI-funded national consortia, we will leverage the results of these innovative studies and integrate them with a broad range of other omics data to realize the goals of improving the diagnosis, precision treatment and ultimate prevention of pulmonary vascular disease.