Rad Modulation of Calcium Homeostatsis as a Putative Therapeutic for Diabetic Cardiomyopathy

Abstract The diabetes mellitus (DM) global patient population exceeds 450 million, and is projected to rise to 693 million by 2045. Type II DM patients (T2DM) show a progression towards heart failure, and DM increases the risk of heart failure by about 2.5-fold. The complex nature of DM cardiomyopathy and the enormous patient population sums to an important unmet need for innovative approaches to understanding and ultimately treatment. This proposal hinges on new findings from my lab focused on L-type calcium channel (LTCC) regulation by Rad. Upon Rad deletion, the heart acquires a chronic, stable gain of function. A common finding in DM cardiomyopathy is reduced calcium homeostasis that can directly track to progression towards heart failure. Recent studies implicated LTCC protein interactions suggesting that loss of Rad specifically might be beneficial for diabetic cardiomyopathic heart. In this pilot proposal we will consider complementary in vivo and in vitro model systems with a single focus on the ability of Rad deletion to improve response of the myocardium to diabetes. First, in vivo mouse models of diabetes will be tested that model Type 1 and a later stage Type 2 diabetes. In parallel, human myocardium will be tested using induced pluripotent stem cell derived cardiomyocytes, and an innovative tissue slice preparation. Results of this pilot project will allow a lab never before involved in diabetes to translate a knowledge base to a new field.