COBRE: W & I HOSP OF RI: SIGNALING PATHWAYS IN CARDIOMYOCYTE PROLIFERATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The growth mode of cardiomyocytes switches from hyperplasia to hypertrophy shortly after birth. The molecular mechanisms responsible for the switch are not well understood. A number of intracellular signal transduction pathways have been suggested to be important in regulation of cardiac growth including the phosphoinositide 3-kinase (PI3K)/p70 S6 kinase (p70S6K) pathway and extracellular signal-regulated kinase 1 & 2 (ERK1,2). We demonstrated a profound reduction in neonatal cardiomyocyte proliferation following b-adrenergic receptor blockade. This effect is associated with reduction in p70S6K activity but not in ERK1,2 activity. These suggest that bAR have an important role in mitogenic signaling and regulation of cardiac growth during fetal and early newborn development. We further demonstrated the ontogeny of p70S6K and PI3K in the heart appears to be synchronized and highly regulated throughout development in the heart. There are high basal levels of cardiac p70S6K and PI3K activity in the late gestation fetus and newborn but not in the adult. The high activities of both kinases occur when cardiomyocytes are undergoing hyperplastic growth. Hence, there is a correlation between p70S6K/PI3K activities and cardiomyocyte growth. Recent advances in genetic techniques have provided valuable experimental tools to answer fundamental biological questions. Conditional expression systems can be developed which allows cardiac-specific overexpression of PI3K at selected time points during development. We will us this approach to examine the role of these pathways at different developmental stages and to determine if post-proliferative cardiomyocytes can be "re-initiated" to undergo cell division under the control of the PI3K. The specific aims in this proposal will 1) characterize the role of beta-1AR regulation of p70S6K/PI3K activity in mouse models with genetically altered beta-AR and PI3K signaling and 2) create a mouse line with conditional overexpression of cardiac PI3K in the heart and characterize its effects on cardiomyocyte proliferation at different stages of development. These studies will contribute to our understanding of the regulation of cardiac growth during the perinatal transition and in pathological conditions during adult life.