Modification of the predisposition for ectopic calcification

About This Grant

PROJECT SUMMARY Cardiac valve and arterial wall calcification are associated with a 3- to 4-fold increased risk of all-cause mortality and catastrophic cardiovascular events such as myocardial infarction and stroke. A number of factors and disease processes predispose to ectopic and vascular calcification, including aging, hypertension, diabetes, and chronic kidney disease. Given the overall aging population and the increasing incidence of these common and chronic conditions, it is imperative to delineate the underlying mechanisms of pathological calcification to better understand inciting events and develop new treatment strategies. Ectopic calcification, once considered passive precipitation of calcium and phosphate, is now recognized as a consequence of dysregulated extracellular ATP metabolism with a reduction of the pyrophosphate/inorganic phosphate ratio. Prior work investigating Mendelian calcification disorders has helped elucidate these mechanisms. By exploring genetic modifiers of these rare conditions, we have the opportunity to discover and leverage potent therapeutic strategies for monogenic, common, and complex presentations of ectopic calcification. Biallelic variants in ABCC6 typically cause pseudoxanthoma elasticum (PXE) which is characterized by elastic fiber calcification in the skin, eyes, and vessels, causing skin laxity, central vision loss, and peripheral arterial disease in the third to fourth decade of life. Interestingly, in approximately 10% of cases, these ABCC6 variants result in generalized arterial calcification of infancy (GACI), a much more aggressive disorder characterized by occlusive arterial calcification causing myocardial infarction, stroke, and death in 50% of patients by 6 months of life. There is no evidence for a genotype-phenotype correlation nor known environmental determinants of disease severity. This striking clinical dichotomy strongly supports the existence of unknown genetic modifiers. To test the central hypothesis that genetic modifiers contribute to this phenotypic variability, an established Abcc6 mouse colony, biobank of patient DNA and cell lines, purine metabolomics, CRISPR gene editing, and computational genomics, will be employed to explore the following specific aims: 1) Determine how genetic background modifies the calcification phenotype in Abcc6-/- mice; 2) Distinguish ABCC6-related phenotypes in vitro to discover and validate potential modifiers; and 3) Identify candidate modifiers in patients with biallelic ABCC6 variants. These studies will define and validate one or more genetic modifiers of the ABCC6-associated calcification disorders PXE and GACI in mice and humans and expose new therapeutic targets to be further investigated in both rare and common calcification disorders.