The Role of ABCC6 In Chronic & Acute Cardiovascular Mineralization

University Of Hawaii At Manoa, Honolulu HI

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Abstract

DESCRIPTION (provided by applicant): Abnormal mineralization occurs in the context of several common conditions, including advanced age, diabetes, hypercholesterolemia, chronic renal failure and certain genetic conditions. Loss-of-function mutations in the ABCC6 gene cause chronic or acute forms of dystrophic mineralization in diseases such as Pseudoxanthoma elasticum (PXE) and dystrophic cardiac calcification (DCC). These pathologies are characterized by mineralization of cardiovascular and/or dermal tissues. PXE is heritable while DCC is an acquired phenotype resulting from cardiovascular insults. We have obtained preliminary data that suggest that ABCC6 initiates and modulates a calcification inhibitor pathway with a crucial role in both acute and chronic dystrophic calcification. We hypothesize that the loss of ABCC6 function in liver produces an imbalance of modulators of calcification in cardiovascular tissues either directly or through increased levels or modification of a circulating factor. To test this hypothesis, we will use a mouse models to characterize the effects of ABCC6 mutations on the structure and function of the protein, determine the response of Abcc6-/- mice to acute ischemic cardiac injuries and determine the role of Abcc6-/- in the calcification of the atherosclerotic plaque.