THE ROLE OF P13 KINASE IN CARDIAC REPAIR AND REMODELING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. It has been demonstrated an important role of ¿1AR signaling in regulation of cardiac myocytes proliferation during the fetal and early postnatal period. We have also demonstrated a constitutively elevated level of signaling of PI3 kinase/P70 ribosomal protein S6 kinase activity (p70 S6K) pathway during the proliferative period of cardiac growth. The dogma of terminal differentiation and absence of cardiomyocytes division in adulthood has been recently challenged. Using unique and well-established stem cell arming strategy, our recent study revealed that intravenously infusion of armed lin-c-kit+ stem cells markedly restored myocardial ventricular function and prevention of cardiac remodeling, which was associated with increase of angiogenesis as well as reduction myocardial apoptosis in infarcted myocardium. Deletion of Akt-1 of stem cells, the known downstream target of ¿1AR /PI3 Kinase signaling, completely eliminated the beneficial effect of stem cells infused in infarcted myocardium, demonstrating a crucial role of Akt-1 in mediating stem cells to produce regenerative capacity. It remains known how these components of this unique signaling mediate the myocardial regeneration. We will examine these questions using a combination of genetically modified animals with overexpression of PI3 kinase p110 alpha, stem cells targeted to antigens expressed by injured myocardium, the assessment of cardiac function and biochemical and genetic studies of regenerated cardiomyocytes. Our specific aims are: 1) Using well-established stem cell arming strategy and myocardial infarction models, we will compare cardiac functional restoration in the damaged heart receiving Lin-c-kit /PI3K-p110 +/+ stem cells with hearts receiving the wild type stem cells; 2) we will examine the impact of Lin-c-kit stem cells over-expressing PI3K-p110 alpha on newly regenerated myocyte and angiogenesis; 3) By taking advantage of unique tTA system in combination with the in vivo condition, we will attempt to define the contribution of the cell fusion to myocardial regeneration and functional restoration and, We will assess whether the PI3K-Akt-1 working model will orchestrate myocardial regeneration following stem cells administration. PI3K+/+-Akt 1-/- Lin-c-kit+stem cells will be generated from double transgenic mice by crossing PI3K+/+ and Akt 1-/- mouse lines.