The overall emphasis of this extension R37 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 both embryonic heart development and during pathological and physiological 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. Over the past 4 years of this award we published several manuscripts that directly addressed each of the 3 original specific aims, including making cardiac-specific Gata4 null mice, Gata6 heart-specific null mice, and inducible transgenic mice that express either GATA4 or GATA6 in the heart. We also generated mice that had a knock-in mutation in Gata4 at serine 105, changing this amino acid to alanine to prevent its phosphorylation and transcriptional induction with hypertrophic stimulation. Our results were published in the very best journals and they established the role that both GATA4 and GATA6 play in the adult heart as necessary transcriptional regulators of the hypertrophic response. We will continue working on all three specific aims in the coming 5 year extension period, as well as add 2 new specific aims to identify additional mechanisms whereby GATA factors regulate cardiac hypertrophy, and to address redundancy between GATA4 and GATA6 in the heart.
The relevance of this extension application is related to the fundamental issue of how the heart hypertrophies in response to disease stimulation in the adult, as well as developmentally, how the myocyte specific gene program is established. A better understanding of these 2 issues should have a profound impact on understanding human disease and suggesting novel treatment approaches for the heart.
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