Sex-dependent cardiac cyclic-AMP signaling and arrhythmias in the failing heart - PROJECT SUMMARY Heart failure (HF) with reduced ejection fraction is a leading cause of death in the US. HF is associated with autonomic dysregulation and significant remodeling of calcium handling, excitation-contraction coupling, and electrophysiology, which collectively lead to contractile dysfunction and increased risk of ventricular arrhythmia. HF incidence and outcomes are strongly sex-dependent; men have a higher incidence of HF, and in patients with non-ischemic cardiomyopathy, women display a lower arrhythmia propensity than men. The precise mechanisms underlying these sex differences and the protection in female hearts remain unclear. Our initial studies discovered regional- and sex-dependent differences in b-adrenergic receptor (b-AR)- cyclic AMP (cAMP) signaling that lead to previously unrecognized functional electrophysiological differences in male and female mice, and could act as a potential anti-arrhythmic mechanism in female hearts. By combining whole- heart, cellular, and subcellular approaches, this project aims to uncover novel mechanisms that underlie sex differences in b-AR-cAMP signaling, which may play a role in sex-dependent outcomes in HF. A multi-level experimental approach will be employed, investigating at the nanoscale, cellular, and whole heart level, to examine: 1) the structural and functional mechanisms underlying sex differences in b-AR-cAMP signaling in the intact heart, and 2) how sex- and region-dependent sympathetic remodeling in HF impacts b-AR-cAMP signaling and arrhythmias. We propose to collaborate with a multidisciplinary advisory team to use novel whole-heart FRET + optical mapping, isolated myocyte experiments, biochemical approaches, and super resolution microscopy to assess cellular and subcellular mechanisms underlying regional- and sex-differences in b-AR- cAMP signaling. How these signaling cascades and functional outputs are remodeled in a rodent model of HF will also be tested. Completion of this proposal will significantly advance our understanding of sex differences in cardiac patho-physiology and may provide insight into new gender-specific therapeutic approaches. UC Davis offers an exceptional training environment for the mentored phase of the award to achieve these goals. Moreover, the proposed research and training plan will significantly contribute to the applicant's personal and professional growth. The mentored phase of this award will provide an invaluable training opportunity to develop a unique scientific and professional skillset necessary to address the goals of this proposal, as well as prepare for independence and make the applicant a competitive candidate for faculty positions. The independent phase of this award will provide time, and funds, to create an independent research program in cardiovascular physiology.
