Autocrine signaling through Gq-coupled receptors is a critical regulatory mechanism for reactive cardiac hypertrophy in the adult heart. Through in vivo and in vitro genetic manipulation of cardiomyocytes receptors or their associated G-proteins and downstream effectors, we have identified signaling events that control pathologic and physiologic myocardial hypertrophy and that activate apoptosis, thereby causing hypertrophy decompensation. Recently ablation of Gq-coupled receptors of Gaq itself has shown that signaling via the Gq pathway is at least as important in the normal development of the embryonic hearts as it is in stimulating pathologic cardiac hypertrophy in the adult. Thus, our GENERAL HYPOTHESIS is that Gaq signaling controls myocardial growth in normal development and reactive myocardial disease by initiating a cascade of biochemical and genetic events culminating in cardiomyocytes growth and/or programed death. Unfortunately, a limitation of all standard transgenic or gene knockout studies of myocardial growth regulators is that overexpression or gene ablation occurs at a time of simultaneous developmental cardiac growth. The superimposition of normal developmental cardiac growth on the experimental genetic perturbation confounds interpretation of studies that have modified Gq signaling effectors in the embryo or neonate. However, second generation systems have recently been developed permitting precise temporal control over transgene expression and gene ablation. Herein, we propose to use such systems to differentiate between the normal and pathophysiological effects of signaling through Gq-PKC with the following SPECIFIC AIMS. SA#1-Determine the effects of increasing Gq/PLC/PKC signaling on myocyte hypertrophy and contractile function in the growing neonatal and the terminally differentiated adult mouse heart through inducible expression of wild type or mutually activated Gaq. SA#2-Determine the effects of enhanced Gq/PLC/PKC signaling on fetal cardiac development through constitutive or inducible cardiac-specific Gaq expression in mouse embryos. SA#3-Establish the roles of PKCdelta and PKC epsilon on cardiac structure and contractile function through inducible, cardiac-specific mutational ablation of their genes in mice. Collectively, these studies will therefore employ state-of-the-art techniques for genetic manipulation and the microphysiologic analysis of adult and embryonic cardiac phenotypes, as well as a genetically unbiased approach to measure myocardial gene expression, to achieve fresh insights into the fundamental mechanisms of myocardial growth in health and disease.
Showing the most recent 10 out of 28 publications
