Research Project
10227925
PROJECT SUMMARY/ABSTRACT The objectives of this proposal are to 1) nurture the development of Dr. Gregory Aubert to become a successful physician scientist investigator in the field of cardiovascular disease with focus on cardiac metabolism, and 2) to better outline the role of the sulfonylurea receptor 2 (SUR2) in the control of cardiomyocyte metabolism under physiological stressors, and more specifically in the development of heart failure. This application has been designed to help Dr. Aubert succeed in his transition to an independent investigator through 1) graduate level and junior faculty coursework in the Loyola Stritch School of medicine and Northwestern Clinical and Translational Sciences Institute and the Interdisciplinary Biological Sciences program 2) development of proficiency in new scientific methods such as human induced pluripotent stem cell (hiPSC) derived cardiomyocyte and gene editing, 3) improvement of skills in scientific communication and translational medicine through structured mentorship. Many current therapies for heart failure are directed at disturbances in the neurohormonal axis and do not directly target the cardiomyocyte. Evidence is emerging that alterations in myocyte energy metabolism and substrate utilization are key components of the heart failure development. Nonetheless, the exact mechanisms leading to this metabolic shift are not well delineated. Human genetic studies have identified mutations in the ABCC9 gene, which encodes SUR2, in the development of dilated cardiomyopathy and ventricular arrhythmias. Mice globally deleted for Abcc9/SUR2 develop heart failure in the neonatal window with a failure to transition normally to oxidative metabolism. Given the role of SUR2 and its partner proteins to modulate cardiac energetics, we believe that this protein could serve as a new target in the treatment of heart failure. The rationale for the proposed research is to better understand SUR2 regulation of cardiomyocyte metabolism in order to manipulate energy expenditure in heart failure. To prove this hypothesis, we will use a genetically engineered mouse model with downregulation of SUR2 as well as human induced pluripotent stem cells-derived cardiomyocytes derived from patients having ABCC9 genetic variants with heart failure and arrhythmia phenotypes. This will provide us with the unique opportunity to corroborate the findings from animals with those from human cardiomyocytes. As a consequence of the work proposed, we expect to determine the cellular and physiological role of SUR2 in rodent and human cardiomyocyte. Combining in vivo genetically modified mouse models and human derived cells is expected to vertically advance understanding of how SUR2 can be better manipulated for therapeutic purpose.
