Protection of myocardial tissue from apoptotic cell death and maladaptive hypertrophic remodeling? are valid approaches to inhibit pathogenesis and slow the transition to heart failure. Despite? increasingly detailed and specific knowledge of survival signaling pathways in the myocardium, the? potential promise of beneficial interventional approaches remains unfulfilled. This failure stems, in? part, from limitations in our current understanding of how cardiomyocytes interpret extracellular? stimuli translate this into advantageous survival signaling in an appropriately regulated fashion. The? long term goal of this study is to understand molecular mechanism(s) responsible for? cardioprotective signaling in cardiomyocytes. The goal of this proposal is to establish the? mechanism of Pim-1-mediated myocardial signaling at multiple distinct life stages, define the role of? Pim-1 expression in response to cardiomyopathic stimuli, demonstrate the consequences of? impaired Pim-1 activity upon cardiomyocyte biology and cardiac function, and determine the? efficacy of interventional approaches to regulate Pim-1-mediated signaling and cardiomyocyte? survival in an appropriately beneficial fashion. Specifically, experiments will determine the? expression of Pim-1 throughout development and aging, assess the effect of altering Pim-1 activity? upon murine models of cardiomyopathy, delineate the relationship between Pim-1 and Akt, and? provide a mechanistic basis for the protective actions of Pim-1 by defining the signaling cascades? potentiated by Pim-1 leading to preservation of mitochondrial integrity. The hypothesis is that Pim-? 1 is a nexus for signaling """"""""life cycle"""""""" control of cardiomvocvtes by influencing proliferation, survival.? and senescence.
Specific aims of the proposal will demonstrate that: 1) Pim-1 regulates postnatal? cardiac development and prolongs cardiomyocyte survival in aging, 2) Pim-1 enhances? cardiomyocyte survival in response to cardiomyopathic challenge, 3) Pim-1 is a critical downstream? effector of activated Akt that confers resistance to apoptosis, and 4) Pim-1 exerts protective effects? through inhibition of mitochondrial death pathways. The innovative approach employed will? involve molecular, biochemical, and microscopic analysis in vitro using cultured cardiomyocytes? together with 'proof of principle' validation using mouse paradigms in vivo. The significance of? these studies is to develop an integrated perspective of myocardial protective signaling that will be? beneficial for the design and implementation of molecular inverventional strategies to treat cell? death and the progression of heart failure.
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