Heart disease is the main contributor of morbidity and mortality in the United States. Currently, pharmacological treatments and procedures are insufficient to restore cardiac integrity and function after a myocardial infarction (MI). Adul stem cell therapy has been approached as an alternative therapy to mitigate heart failure after acute damage. Cardiac progenitor cells (CPCs) can be isolated and expanded ex vivo from patients and applied to the heart after MI to confer improvements in cardiac function, yet the effects are modest due to poor survival, limited engraftment and cardiac specific commitment within the infarcted region. Genetic modification strategies have been approached to improve cardiogenic differentiation of stem cells ex vivo to promote superior regeneration in vivo. Calcium/Calmodulin Kinases II (CaMKII) is regulated by increases in intracellular calcium in cardiomyocytes and smooth muscle cells. However, the role of individual CaMKII isoforms and splice variants in CPCs has not been explored. CaMKIIB is the predominant nuclear splice variant in the adult heart, regulating hypertrophic gene expression, cellular proliferation and apoptosis. In preliminary experiments, CPCs express CaMKII splice variants during basal conditions, which may be regulated differentially by acquisition of a more committed phenotype. Lentiviral over-expression of CaMKIIB in CPCs enhances formation of cells into the cardiac and smooth muscle lineage in vitro. Additionally, CaMKIIB in CPCs promotes changes in cell morphology and decreases proliferation but is protective from cell death. Therefore, we hypothesize that modified CPCs with CaMKIIB will display enhanced survival, engraftment and cardiac lineage commitment after delivery into the acute ischemic heart. Initial reports support that engineered CPCs show increased protection from cell death and enhanced differentiation, therefore CPCs modified with CaMKIIB will promote superior improvements in cardiac function and myocardial structural integrity compared to control CPCs. This research plan will analyze the contribution of CPCs over-expressing CaMKIIB to not only promote direct regeneration of the damaged regions but also stimulate endogenous reparations from resident c-kit positive cells. In conclusion, this study will enhance our knowledge of calcium- regulated proteins such as nuclear CaMKII in CPCs to promote cardiac specific regeneration and effectively prevent heart failure after an acute MI.
CaMKII?B, the predominant nuclear splice variant in the adult heart, regulates hypertrophic gene expression and is protective from apoptotic stress agents when over-expressed in cardiomyocytes. To demonstrate the effectiveness of these cells as a therapy, an in vivo delivery approach was designed to assess if enhanced CPCs will improve myocardial function and structure after acute MI by stimulating cardiac regeneration. The goal of this project is to advance cellular therapy using CPCs and define a novel molecule to promote efficient cardiac commitment that is necessary to prevent heart failure.
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