Role of Sphingolipid pathways in the pathobiology of PAH

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ABSTRACT Pulmonary arterial hypertension (PAH), a rare, debilitating and fatal disease for which there is currently no available cure. There is compelling evidence that the Sphingosine kinase1/S1P signaling axis is a novel and therapeutic target for PAH. To facilitate the translation of current in vivo and in vitro observations on the role of S1P dependent signaling in PAH pathobiology, this proposal will explore the hypothesis that the Sphingosine kinase1/S1P signaling axis regulates physiologic, cellular and molecular pathways in PAH that result in pulmonary vascular remodeling. SA1 seeks to define the role of LncRNA Khps1 in miR-1 and SPHK1 expression and promoting pulmonary vascular remodeling. SA2 seeks to define molecular mechanisms by which LncRNA Khps1/SPHK1 regulate pulmonary artery smooth muscle cell mitochondrial dynamics. SA3 will investigate the role of SPHK1 in aberrant chromatin remodeling and gene expression in the development of pulmonary vascular remodeling.