The Program Project Grant will integrate aspects of signal transduction that underlie normal and abnormal cardiovascular function. Gain- and loss-of-function approaches include cell culture, gene targeting and cardiac-specific transgenesis. Signaling pathways in normal cardiac development and function, the basic biology of cardiac signal transduction, as well as the actions on the final targets will be studied. The Program consists of 4 Subprojects and 3 Cores. Subproject 1: Phosphorylation and function of the contractile proteins focuses on the myofibrillar proteins, exploring how the contractile apparatus is tuned to match prevailing conditions. Using cardiac specific transgenesis, proteins in which the relevant sites are modified such that they cannot be phosphorylated, or act as if they were chronically phosphorylated, will replace the endogenous TnI or MyBP-C protein complements. Subproject 2: The calcineurin/NFAT pathway in heart development will explore the regulatory cascades that control differential gene expression and morphogenesis of the developing heart to determine if calcineurin signaling through the NFAT family of transcription factors drives programmatic changes in contractile protein gene expression during cardiac development. Suproject 3: The ERK-MAPK signaling branch in the heart will explore the ERK-MAPK pathway's role in inducing cardiac hypertrophy and promoting protection from apoptotic stimuli. The hypertrophic potential of MEK1 dominant negative mice and ERK1 knockout mice will be characterized. The role ERK-MAPK pathway's role in cardioprotection will be analyzed as will the transcriptional mechanism whereby MEK1-ERK1/2 signaling mediates cardiac hypertrophy. Subproject 4: Rab GTPase protein transport regulation in heart disease. The Rab protein family controls subcellular protein trafficking and the individual actions of myocardial Rab proteins will be explored in the heart using gain-of-function approaches in both cardiomyocytes and in transgenic animals. The Administrative Core (A) will serve as the organizational focus, The Histo-Pathology/Physiology Core (B) will provide an integrated central facility for the necessary histology and pathology, as well as for the physiological analyses. The Adenovirus Core (C) will prepare virus for subprojects 2, 3 and 4, and neonatal rat cardiomyocytes, which will be needed for subprojects 3 and 4.
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