The myocardium is largely unable to effecfively repair itself following an infarcfion. 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 potenfial cardiomyogenic differentiation of CPCs, thereby limlfing 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 differenfiated cardiac myocytes to withstand the violent environment of the post-ischemic myocardium. Protein 0-GlcNAcylafion occurs in every mulficellular 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 regulafing 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 differenfiafion (Aim 3). This Project will use an exhausfive 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 exclfing area of cardiovascular medicine because of the significance of the quesfions being pursued. Project 3 will confinue to collaborate with Projects 1, 2, and 4 to understand innovafive 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 innovafive insights into the regulation of the proliferation, survival, and dlfferenfiation 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.
|Dassanayaka, Sujith; Jones, Steven P (2014) O-GlcNAc and the cardiovascular system. Pharmacol Ther 142:62-71|
|Leri, Annarosa; Rota, Marcello; Hosoda, Toru et al. (2014) Cardiac stem cell niches. Stem Cell Res 13:631-46|
|Sansbury, Brian E; DeMartino, Angelica M; Xie, Zhengzhi et al. (2014) Metabolomic analysis of pressure-overloaded and infarcted mouse hearts. Circ Heart Fail 7:634-42|
|Zavadzkas, Juozas A; Stroud, Robert E; Bouges, Shenikqua et al. (2014) Targeted overexpression of tissue inhibitor of matrix metalloproteinase-4 modifies post-myocardial infarction remodeling in mice. Circ Res 114:1435-45|
|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|
|Iso, Yoshitaka; Rao, Krithika S; Poole, Charla N et al. (2014) Priming with ligands secreted by human stromal progenitor cells promotes grafts of cardiac stem/progenitor cells after myocardial infarction. Stem Cells 32:674-83|
|Watson, Lewis J; Long, Bethany W; DeMartino, Angelica M et al. (2014) Cardiomyocyte Ogt is essential for postnatal viability. Am J Physiol Heart Circ Physiol 306:H142-53|
|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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