The overall theme of this renewal application is to understand the molecular pathways that control cardiac gene expression and the hypertrophic growth of the myocardium. The focus of this proposal is to analyze the GATA4, 5, and 6 transcription factor family as regulators of the cardiac gene program during both embryonic development and during pathophysiologic growth of the adult heart. GATA factors are known to directly regulate the expression of most cardiac-expressed structural genes, thus facilitating the differentiation of cardiomyocytes during early heart development. In the adult heart, GATA4 and GATA6 transcription factors are re-employed where they function as important regulators of the hypertrophic gene program in response to pathophysiologic stimulation. Indeed, the hypertrophic response of the adult heart involves re-expression of many fetal genes, suggesting that the developmental and disease gene programs share common regulatory events, potentially through GATA4/5/6. Our unifying hypothesis states that GATA4, 5, and 6 are required for both the establishment and maintenance of the cardiac differentiation-specific gene program as well as the growth response of the adult heart during stress stimulation. Previous attempts to define the importance of GATA factors as regulators of the cardiac gene program involved a traditional loss-of-function approach in gene-targeted mice. However, this approach was largely uninformative due to early embryonic lethality and genetic redundancy issues. Here Cre-lox technology will be employed in conditionally targeted GATA4 and GATA6 mice to produce tissue-specific and temporally regulated gene inactivation in the heart. Using these genetically modified models, specific aim #1 will investigate the importance of GATA factors as regulators of the differentiation-specific program during embryonic heart development.
Specific aim #2 will determine the requirement of GATA4 as a mediator of the hypertrophic reponse in the adult heart. Finally, specific aim #3 will examine the mechanism whereby MAPK signaling pathways regulate GATA4/6 during the hypertrophic response. Taken together, an understanding of the regulatory networks that control cardiac differentiation-specific gene expression at steady state and in response to stress will be instrumental in dissecting the transcriptional networks that act during various forms of heart disease in both the developing and adult heart. ? ?
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