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.
| Parker, Sarah J; Stotland, Aleksandr; MacFarlane, Elena et al. (2018) Proteomics reveals Rictor as a noncanonical TGF-? signaling target during aneurysm progression in Marfan mice. Am J Physiol Heart Circ Physiol 315:H1112-H1126 |
| Broughton, Kathleen M; Wang, Bingyan J; Firouzi, Fareheh et al. (2018) Mechanisms of Cardiac Repair and Regeneration. Circ Res 122:1151-1163 |
| Broughton, Kathleen M; Sussman, Mark A (2018) Enhancement Strategies for Cardiac Regenerative Cell Therapy: Focus on Adult Stem Cells. Circ Res 123:177-187 |
| Gude, Natalie A; Sussman, Mark A (2018) Chasing c-Kit through the heart: Taking a broader view. Pharmacol Res 127:110-115 |
| Yu, Olivia M; Benitez, Jorge A; Plouffe, Steven W et al. (2018) YAP and MRTF-A, transcriptional co-activators of RhoA-mediated gene expression, are critical for glioblastoma tumorigenicity. Oncogene 37:5492-5507 |
| Gude, Natalie A; Firouzi, Fareheh; Broughton, Kathleen M et al. (2018) Cardiac c-Kit Biology Revealed by Inducible Transgenesis. Circ Res 123:57-72 |
| Shires, Sarah E; Gustafsson, Åsa B (2018) Regulating Renewable Energy: Connecting AMPK?2 to PINK1/Parkin-Mediated Mitophagy in the Heart. Circ Res 122:649-651 |
| Woodall, Benjamin P; Gustafsson, Åsa B (2018) Mesenchymal Stem Cell-Mediated Autophagy Inhibition. Circ Res 123:518-520 |
| Lampert, Mark A; Gustafsson, Åsa B (2018) Balancing Autophagy for a Healthy Heart. Curr Opin Physiol 1:21-26 |
| Kubli, Dieter A; Sussman, Mark A (2018) Editorial commentary: Mitochondrial autophagy in cardiac aging is all fluxed up. Trends Cardiovasc Med 28:261-262 |
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