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Urinary stone disease (USD) is a debilitating disorder that affects 1 in 11 Americans. More than 80% of the analyzed stones have calcium oxalate (CaOx) in their composition. Previous studies have shown commonalities in the development of Randall’s plaque calcium oxalate stones and arterial calcifications. In an innovative approach, with a pro-atherogenic APOE knock-out model, we observed that when given a highoxalate diet, animals simultaneously exhibit enhanced atherogenic potential and the development of either urinary tract stones or a renal oxalosis dependent on administration of an antibiotic cocktail. The results from this animal study corroborates clinical genome-wide association studies which show that single nucleotide polymorphisms variations in the APOE gene is strongly associated with kidney stone formation. Our findings support the hypothesis of a common pathway for the development of atherosclerosis and CaOx stones. In this proposal, we will pursue proof of concept studies to optimize a mouse model that develops both disorders through a common dietary intervention. To achieve this, we will run a trial with conventionalized, specific pathogen free APOE knock-out mice. Mice will be given different concentrations of dietary oxalate to induce the atherosclerosis-kidney stone phenotype at different stages of development and disease severity. Thus, our expected breakthrough discovery will be the establishment of a proatherogenic and prolithogenic co-morbid mouse model that closely aligns with the genetic and phenotypic predispositions seen in the human population. This high-risk/high reward proposal has a strong potential to reveal common pathways for the development of USD and CVD. This knowledge can provide the base for potential preventative or disease modulating measures in these co-occurring disorders.
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