Calcification-Omics, Molecular Elucidation, & Therapeutics (COMET)

• Rajeev MALHOTRA, Massachusetts General Hospital (USA)
• Catherine SHANAHAN, King's College London (UK)

Vascular calcification is a global health burden contributing to a multitude of cardiovascular diseases including atherosclerotic cardiovascular disease, arterial stiffness with associated hypertensive heart disease, and small vessel disease such as calciphylaxis. There is no targeted therapy for vascular calcification, which is becoming increasingly prevalent due to population aging and increases in worldwide cases of diabetes and chronic kidney disease. Vascular smooth muscle cells (VSMCs) are central players in orchestrating the calcification process which is regulated by both biological and physicochemical pathways. Key mechanisms of calcification include loss of endogenous inhibitors, VSMC osteogenic differentiation and mineral nidus formation, with metabolic stress and aging as key drivers of these processes. Despite these advances in mechanistic understanding, the development of therapeutics requires further detailed knowledge of (1) culprit VSMC sub-populations in different disease contexts, (2) identification of new candidates to target and (3) how cross-talk between aging VSMCs and the aging extracellular matrix (ECM) environment in the vascular niche impacts cell phenotype and nidus formation. With these aims in mind, this network will focus on the function of newly identified genetic and multi-omic targets for calcification, use transcriptomics to dissect VSMC heterogeneity and signaling pathways in the calcification niche, and apply chemistry and proteomics approaches to understand ECM modifications and how they impact physicochemical properties of mineralization. These data will feed into candidate and AI-based therapeutic approaches aimed at modulating calcification both in rare genetic conditions of calcification and in more common cardiovascular diseases of the general population. This ambitious interdisciplinary and multi-faceted project requires the expertise of cardiologists, nephrologists, biotechnologists, biologists, and chemists to develop novel targeted therapies for patients suffering from vascular calcification. The passion that drives this project results from a simple emerging hypothesis: it is possible to reduce cardiovascular morbidity and mortality by targeting vascular calcification.