Preservation of mitochondrial integrity by Pim-1

San Diego State University, San Diego CA

Investigators

Linked publications & trials

Abstract

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