Novel Molecular Regulators of Vascular Calcification

项目总结

PROJECT SUMMARY Atherosclerotic disease is characterized by intimal vascular calcification, which is an independent and potent risk factor for morbidity and mortality in coronary artery disease, stroke, and aortic pathologies. Vascular calcification is an active cell-mediated process that involves the phenotypic switch of vascular smooth muscle cells (VSMC) from contractile to osteogenic cells. Understanding the molecular mechanisms driving vascular calcification is critical for developing targeted therapies. In our lab, we have identified novel single nucleotide polymorphisms (SNPs) in the arylsulfatase E (ARSE) locus on the X chromosome that are associated with coronary artery calcification. Our preliminary data demonstrate that adenovirus-mediated overexpression of ARSE in VSMCs leads to increased calcification and that conversely, reduced expression of ARSE with siRNA prevents calcification of VSMCs. We have identified SULF1, a protein related to ARSE in the same family of sulfatases, as having similar effects on vascular calcification as that demonstrated in our in vitro studies for ARSE. Based on our previous studies, we have also identified histone deacetylase 4 and 5 (HDAC4/5) to be important regulators of vascular calcification, mediated by subcellular localization of HDAC4/5 in the cytosol through phosphorylation by focal adhesion kinase (FAK). The goal of this project is to perform in vitro, ex vivo, and in vivo studies to test the hypothesis that ARSE/SULF1 and HDAC4/5 are important and novel determinants of vascular calcification that induce the phenotypic switch of VSMCs to osteogenic cells. Overall, my aim is to unravel novel molecular mechanisms underlying VSMC function and calcification that contribute to the pathogenesis of atherosclerotic cardiovascular disease. Through world-class didactic opportunities and close mentorship from experts in the field of vascular biology and genomics, I will complete this project having gained valuable skills in bioinformatics, in vitro cellular assays modeling vascular disease, in vivo mouse model experiments, scientific communication and laboratory leadership. By the end of the fellowship, I will have gained skills necessary to develop my own research program and ultimately launch my own career as an NIH-funded vascular surgeon scientist.