A Critical TAK1 Signaling Network in Myocardial Survival and Remodeling

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DESCRIPTION (provided by applicant): Identification of the signaling networks that mediate cardiac myocyte growth, cell death, and pathological remodeling is critical to the ultimate elucidation of the molecular basis of heart failure. The long-term goal is to define novel molecular signaling mechanisms regulating cardiac remodeling and heart failure and to determine how they can be targeted for the treatment of myocardial diseases. Preliminary studies in this application identify a novel TAK1 (TGFß-activated kinase 1, also termed MAP3K7) signaling network that is essential for cardiac cell survival and homeostasis. The functional roles of TAK1 signaling in the heart and its implications in heart disease are largely not known, nor is the mechanism of action understood. The central hypothesis is that the novel cardioprotective TAK1 signaling network is critically involved in cardiac myocyte survival and the maintenance of normal cardiac structure and function, thereby preventing pathological cardiac remodeling and heart failure progression. The objective of this application is to evaluate physiologic functions of the TAK1 signaling network in the heart and its role in the pathogenesis of adverse cardiac remodeling and failure, by using integrated molecular, genetic, and functional approaches, as well as unique genetically modified mice developed by this research team. Guided by strong preliminary data, this hypothesis will be tested by pursuing 3 specific aims: 1) To investigate the essential role of TAK1 in regulating cardiac cell survival and myocardial homeostasis in vivo. 2) To determine if activation of TAK1 is sufficient to protect the heart from adverse remodeling and failure through promoting cell survival. 3) To determine the molecular mechanisms underlying TAK1-dependent cardioprotection and its role in regulating cardiac cell death and myocardial remodeling. First, the physiologic necessity of TAK1 in regulating cardiac cell survival and myocardial homeostasis will be examined using cardiac-specific TAK1 knockout mice. Next, the cardioprotective potential of tetracycline- inducible transgenic expression of TAK1 will be evaluated in mouse models of heart failure. Finally, mechanisms underlying TAK1-mediated cardioprotection and its potential crosstalk with other cell death/survival signaling pathways will be investigated using molecular and genetic approaches. These studies will uncover new mechanistic perspectives from which heart failure can be approached therapeutically and provide candidates for pharmacologic and genetic targeting. Furthermore, the proposed research will be of significance because what is learned here will also contribute to improved understanding of cell survival and homeostatic regulation in other cellular systems and disease models.