A Critical TAK1 Signaling Network in Myocardial Survival and Remodeling

描述（由申请人提供）：鉴定介导心肌细胞生长、细胞死亡和病理重塑的信号网络对最终阐明心力衰竭的分子基础至关重要。长期目标是确定调节心脏重塑和心力衰竭的新分子信号机制，并确定它们如何靶向治疗心肌疾病。该应用程序的初步研究确定了一种新的TAK1 （tgf ß-活化激酶1，也称为MAP3K7）信号网络，该信号网络对心脏细胞存活和稳态至关重要。TAK1信号在心脏中的功能作用及其在心脏病中的意义在很大程度上尚不清楚，其作用机制也不清楚。核心假设是，新的心脏保护信号网络TAK1在心肌细胞存活和维持正常心脏结构和功能中起关键作用，从而防止病理性心脏重塑和心力衰竭进展。本应用程序的目的是评估TAK1信号网络在心脏中的生理功能及其在不良心脏重构和衰竭发病机制中的作用，通过综合使用分子，遗传和功能方法，以及该研究小组开发的独特转基因小鼠。在强有力的初步数据的指导下，我们将通过三个具体目标来验证这一假设：1)研究TAK1在体内调节心肌细胞存活和心肌稳态中的重要作用。2)确定TAK1的激活是否足以通过促进细胞存活来保护心脏免受不良重构和衰竭。3)确定tak1依赖性心脏保护的分子机制及其在调节心肌细胞死亡和心肌重构中的作用。首先，TAK1在调节心脏细胞存活和心肌稳态中的生理必要性将通过心脏特异性TAK1基因敲除小鼠进行研究。接下来，将在小鼠心力衰竭模型中评估四环素诱导的TAK1转基因表达的心脏保护潜力。最后，tak1介导的心脏保护机制及其与其他细胞死亡/生存信号通路的潜在串扰将通过分子和遗传方法进行研究。这些研究将揭示新的机制视角，从中可以治疗心力衰竭，并为药理学和基因靶向提供候选药物。此外，所提出的研究将具有重要意义，因为在这里学到的东西也将有助于提高对其他细胞系统和疾病模型中细胞存活和稳态调节的理解。

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.