The myocardium is largely unable to effectively repair itself following an infarction. Recent work indicates that resident cardiac progenitor cells (CPCs) represent an under-developed therapeutic target. Unfortunately, the post-ischemic myocardium is an unfavorable environment for the survival and potential cardiomyogenic differentiation of CPCs, thereby limiting effective post-ischemic myocardial repair of exogenously administered CPCs. Project 3 will address the biological regulation of stress signaling and its impact on CPC function. Recently, several reports indicated a unique stress response (0-GlcNAc) in the heart that allows differentiated cardiac myocytes to withstand the violent environment of the post-ischemic myocardium. Protein 0-GlcNAcylafion occurs in every multicellular organism that has been examined;yet, nothing is known about the role of this stress signal in CPCs. This Project will directly address this deficiency to create new biological insights. Project 3 will test the central hypothesis that a unique alarm signal (0-GlcNAc) plays a fundamental role in regulating CPC function and that it promotes CPC survival, but may limit bona fide post-ischemic cardiomyogenesis by maintaining CPCs in a persistent state of alarm. Project 3 will establish the impact of the pro-adaptive stress signal, 0-GlcNAc, on CPC function by specifically focusing on proliferation (Aim 1), survival (Aim 2), and differentiation (Aim 3). This Project will use an exhaustive series of carefully controlled loss- and gain-of-function approaches. Regardless of the specific outcomes of the Alms, this Project will provide completely novel Insights into an exciting area of cardiovascular medicine because of the significance of the questions being pursued. Project 3 will continue to collaborate with Projects 1, 2, and 4 to understand innovative inter-regulatory mechanisms between O- GlcNAcylation and: the NO-CO axis (Project 1), TNF-NFkB induced inflammation (Project 2), and hyperglycemic suppression of CPC function (Project 4). The role of protein 0-GlcNAcylafion in CPCs is completely unknown. This Project will undoubtedly establish new biological insights by assuming an innovative approach to understanding CPC regulation and pathophysiology.
Project 3 will establish completely innovative insights into the regulation of the proliferation, survival, and differentiation of primitive cells in the heart and translate the findings into a clinically relevant model of heart failure. Regardless of the specific outcomes of the Aims, Project 3 will provide completely novel insights into a unique form of stress signaling as a previously unrecognized regulator of progenitor cell function.
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|Muthusamy, Senthilkumar; DeMartino, Angelica M; Watson, Lewis J et al. (2014) MicroRNA-539 is up-regulated in failing heart, and suppresses O-GlcNAcase expression. J Biol Chem 289:29665-76|
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|Signore, Sergio; Sorrentino, Andrea; Ferreira-Martins, João et al. (2014) Response to letter regarding article "Inositol 1,4,5-trisphosphate receptors and human left ventricular myocytes". Circulation 129:e510-1|
|Sansbury, Brian E; Hill, Bradford G (2014) Regulation of obesity and insulin resistance by nitric oxide. Free Radic Biol Med 73:383-99|
|Ismahil, Mohamed Ameen; Hamid, Tariq; Bansal, Shyam S et al. (2014) Remodeling of the mononuclear phagocyte network underlies chronic inflammation and disease progression in heart failure: critical importance of the cardiosplenic axis. Circ Res 114:266-82|
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