Molecular and Cellular Regulation of Vascular Calcification

Project Summary Inappropriate accumulation of calcium phosphate salts in cardiac valve and vasculature, also known as vascular calcification (VC), is increased with age, specific genetic disorders, coronary artery disease, valve disease, diabetes and chronic kidney disease. Calcification of these normally compliant organs has severe impacts on hemodynamics and cardiovascular function due to increased stiffness and/or tendency to rupture. There are currently no pharmacological therapies approved to directly prevent or treat VC despite the recognized deleterious effects of calcification in blood vessels and valves. Over the last 20 years paradigm-shifting studies have revealed some of the key genetic pathways, cell types and pathobiological processes that control the initiation and progression of VC These studies indicate that rather than a degenerative, untreatable inevitability, VC is a regulated and potentially modifiable process. The challenge is to understand which pathobiological processes predominate under specific disease conditions, and the critical upstream and downstream signaling pathways regulating them in order to identify biomarkers and target for therapeutic development. The overall goal of my research is to generate new scientific knowledge regarding the pathobiological mechanisms at play in diabetes and chronic kidney disease, highly prevalent diseases with extremely high risk for VC and its complications. We will continue to use a human first approach to identify key risk factors that may play a causative role in VC, and mechanistic studies in animal models, organoids, and cell culture experiments to identify key signaling pathways involved. The proposed studies will facilitate identification of biomarkers, therapeutic targets and therapies to treat this silent killer and improve human health.