A Critical TAK1 Signaling Network in Myocardial Survival and Remodeling

描述(由申请人提供)：识别介导心肌细胞生长、细胞死亡和病理重塑的信号网络对于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构和心力衰竭的新的分子信号机制，并确定如何将它们作为治疗心肌疾病的靶点。在这一应用中的初步研究发现了一个新的TAK1(转化生长因子激活的激酶1，也称为MAP3K7)信号网络，它对心肌细胞的生存和动态平衡是必不可少的。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。中心假说是，新的心脏保护性TAK1信号网络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构和心力衰竭进展。这项应用的目的是评估TAK1信号网络在心脏中的生理功能，以及它在不利的心脏重构和衰竭的发病机制中的作用，通过集成的分子、遗传和功能方法，以及该研究团队开发的独特的转基因小鼠。在强大的初步数据的指导下，这一假说将通过追求3个具体目标来检验：1)研究TAK1在体内调节心肌细胞存活和心肌内稳态中的重要作用。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的影响。3)探讨TAK1依赖的心肌保护机制及其在调控心肌细胞死亡和心肌重塑中的作用。首先，将使用心脏特异的TAK1基因敲除小鼠来研究TAK1在调节心肌细胞存活和心肌内稳态方面的生理学必要性。接下来，将评估四环素诱导的TAK1转基因表达在心力衰竭小鼠模型中的心脏保护潜力。最后，TAK1介导的心脏保护的潜在机制及其与其他细胞死亡/生存信号通路的潜在串扰将使用分子和遗传方法进行研究。这些研究将揭示新的治疗心力衰竭的机制角度，并为药物和基因靶向提供候选。此外，这项拟议的研究将具有重要意义，因为这里所学到的也将有助于更好地理解其他细胞系统和疾病模型中的细胞存活和动态平衡调节。

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.