Many forms of cardiovascular disease are characterized by the progressive loss of cardiac myocytes. Although there is some controversy regarding the level at which adult mammalian cardiomyocytes can reenter the cell cycle, as well as the level at which cardiomyogenic stem cells may repopulate the adult heart, the vast majority of experimental data suggests that these are rather rare events. In light of this, the ability to promote regenerative growth of adult cardiomyocytes could be of therapeutic value. To accomplish this, however, requires the identification of the gene products and/or cytokines that regulate cardiomyocyte proliferation and terminal differentiation. It is now well established that proteins which bind to the SV40 Large T Antigen oncoprotein are frequently cell cycle regulators Studies performed during the current funding cycle through the support of HL45453 have identified, isolated and cloned the cardiomyocyte T Antigen binding proteins. These studies have shown that there are three predominant T Antigen binding proteins. They are p 107 (a member of the RB family which is involved in regulating transit through G1/S), p53 (a tumor suppressor protein which is a major mediator of apoptosis), and p193 (a novel member of the BH3-only pro-apoptosis family). Additional studies have shown that abrogation of the p53 and p193 proapoptotic pathways is critical for sustained cell cycle activity in response to oncoprotein expression in cardiomyocytes. The use of transgenic mice has revealed that abrogation of the p53 and p193 pathways is cardioprotective in adult hearts in vivo. In this competitive renewal application, we propose to further test and challenge these hypotheses.
In Aim 1, we will continue to characterize the cardioprotective phenotype in transgenic mice that express genes encoding dominant interfering p53 and p193 activity, and furthermore will test the hypothesis that a similar protective phenotype can be obtained in cardiomyocytes in which the p193 gene is ablated.
In Aim 2 we will test the hypothesis that abrogation of p193 and p53 activity will render adult cardiomyocytes responsive to cell cycle induction.
In Aim 3 we will identify and clone the cardiomyocyte p 193 binding proteins. Finally, in Aim 4 we will continue to characterize the functional and developmental importance of p193 using knockout animals that have recently been generated. If the putative regulatory roles are validated, these proteins may serve as intracellular targets for therapeutic myocardial growth in the adult heart, as well as potential therapeutic targets to promote cardioprotection. ? ?
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