Project Summary/Abstract My major research focus is to understand the fundamental mechanisms of gene regulation and function in the development of cardiovascular disease, a major health burden for our veterans. Our overarching goals are to translate the findings into identification of novel molecular targets and strategies for prevention and intervention of cardiovascular disease. We have been studying the molecular regulation of vascular smooth muscle cells (VSMC) phenotypic transitions, which should provide new insights into the understanding of the development of atherosclerosis, diabetic vasculopathy and vascular aging. Using novel tissue-specific gene knockout mouse models, we have uncovered an essential role of the osteogenic transcription factor Runx2 in regulating VSMC reprogramming into bone-like cells, leading to the pathogenesis of vascular calcification and stiffness in animal models of atherosclerosis and diabetes. We have also uncovered novel mechanisms underlying Runx2 upregulation in the vasculature by increased oxidative stress and hyperglycemia; and discovered a Runx2- dependent crosstalk between VSMC, macrophages and vascular stem cells in the development of atherosclerotic calcification. With these innovative research programs, I have been able to provide training and mentoring to many graduate students, postdoctoral fellows and junior scientists and physicians at the Birmingham VAMC and affiliated University of Alabama at Birmingham (UAB). Our efforts to investigate the underlying mechanisms and identify targets for cardiovascular disease have brought together increasing numbers of physician scientists and basic scientists at the Birmingham VA medical center and UAB, which led to the development of a VA-funded Program Project Award and three of my Merit Review Awards, including the exciting and highly VA-related research “Molecular Regulation of Vascular Calcification in Diabetes” (2019- 2023). In addition, our collaborative research projects on the regulation of VSMC function in atherosclerosis, diabetes and vascular aging have also been supported by several R01 grants from the National Institutes of Health. These ongoing investigations will not only elucidate the molecular mechanisms underlying the pathogenesis of vascular disease and aging, but also provide novel molecular insights facilitating further studies to translate these findings into therapeutic strategies for patient care, so as to improve the veterans’ health, life span and quality of life, as well as reduce healthcare costs.