Differential regulation of hypertrophy and apoptosis by beta adrenergic signaling in cardiac myocytes. Heart failure is the leading cause of death. Increased beta-adrenergic (?A) signaling contributes to heart failure through simultaneous yet differential regulation of hypertrophy and apoptosis in myocardial tissue. These combined responses result in pathologic hypertrophy preceding heart failure. Understanding how ?A signaling differentially regulates the hypertrophic and apoptotic signaling networks may yield new therapeutic targets for treatment of heart failure and also yield insight into the mechanism of differential regulation of multiple phenotypes by a single stimulus.
In Aim 1, while previous studies have separately demonstrated ?A-induced hypertrophy or apoptosis, this proposal will investigate the heterogeneous cell decision-making process between hypertrophy and apoptosis using FRET biosensors of apoptotic activity and pharmacological and genetic perturbations to the combined ?A-hypertrophic-apoptotic signaling network. This approach represents a novel experimental paradigm to simultaneously monitor both phenotypes at the single cell level.
In Aim 2, this proposal will reconstruct and independently validate a computational model of the cardiac ?A- hypertrophic-apoptotic signaling network to develop a mechanistic understanding of the differential regulation of hypertrophy and apoptosis. Collectively, these studies are both hypothesis-testing and hypothesis-generating and I expect these studies to identify and validate new pharmacological targets for the improved treatment of heart failure.
Differential regulation of hypertrophy and apoptosis by beta adrenergic signaling in cardiac myocytes. Heart failure is a leading cause of mortality. This study focuses on how a biochemical signaling pathway exacerbates heart failure by activating multiple other signaling pathways that simultaneously but separately contribute to growth and death of heart muscle. By using a combination of experimental methods to simultaneously measure growth and death of heart cells in response to activation of this pathway and computational methods to simulate the interconnected signaling network that underlie this growth or death, this proposal will identify novel potential therapeutic options to modulate the balance of growth and death in the heart.
