Pilot Project for Peter Kekenes-Huskey: Computational Examination of Calcium Signaling in Remodeled Cardiac Myocytes

Diabetes is a prominent risk factor for cardiovascular disease in the growing obese population. The progression from pre-diabetes to diabetic cardiomyopathy entails a complex and poorly understood destructive interplay between dysregulated Ca2+ signaling and severe morphological changes in cardiac cell structure. Quantitative knowledge of how etiology-specific changes in heart cell ‘ultra- structure’ couple to dysregulated Ca2+-dependent cardiac signaling could offer new strategies to fight heart disease at the molecular level. The primary goals of this pilot project is to develop new computational tools to characterize transverse tubule (TT) ultra-structure remodeling from representative cardiac phenotypes disease models and test hypotheses that relate distinguishing TT features to intracellular Ca2+ dysregulation, with specific focus on rat models of type II diabetes. Our aims outline algorithmic innovations to address these limitations, using high resolution cardiomyocyte structural and function imaging data from rat cardiac ventricular myocytes combined with system biological models of calcium handling: - Aim 1 Test the hypothesis that remodeled TT present disease-specific morphologies and spatial heterogeneity that is detectable via advanced image detection algorithms. - Aim 2 Test the hypothesis that Ca2+ release amplitude, duration and synchrony correlate with distinct, disease-dependent patterns of TT remodeling. Ultimately these studies will foster improved mechanistic understanding of relationships between cardiomyocyte Ca2+ signaling and ultra-cellular structure.