Mechanisms driving cardiac dysfunction in Autosomal Dominant Polycystic Kidney Disease

The project aims to determine how ADPKD-causing PC1 mutations disrupt PC1 actions in cardiomyocytes, impair cardiac function, and predispose the heart to hypertension-induced heart failure, independent of renal dysfunction. Specific aims include: 1) determining how PC1 mutations affect action potentials and Kv channel activity, and their impact on calcium handling and contractility; 2) elucidating mechanisms by which PC1 regulates sarcoplasmic reticulum (SR) calcium loading and SERCA to maintain cardiomyocyte function, and testing the impact of ADPKD mutations on these events; and 3) determining in vivo whether alterations in PC1 signaling in cardiomyocytes drive cardiac dysfunction and predispose the heart to hypertension-induced heart failure.