A Critical TAK1 Signaling Network in Myocardial Survival and Remodeling

心肌存活和重塑中关键的 TAK1 信号网络

• 批准号: 8770054
• 负责人: Qinghang Liu
• 金额: $ 38.05万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-17 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8770054
• 关键词: Address; Adult; Apoptosis; Binding; Biological Process; Bypass; Calcineurin; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Death; Cell Death Signaling Process; Cell Differentiation process; Cell Survival; Cells; Cessation of life; Complex; Cues; Data; Development; Disease model; Failure; Fibrosis; Gap Junctions; Genetic; Goals; Growth; Health; Heart; Heart Diseases; Heart failure; Homeostasis; Human; Hypertrophy; Immune Cell Activation; In Vitro; Inflammation; Inflammatory; Interleukin-1; Interleukin-18; Knockout Mice; Knowledge; Learning; MAP Kinase Gene; MAP3K7 gene; Maintenance; Mediating; Membrane; Mission; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Genetics; Mus; Muscle Cells; Myocardial; Myocardial dysfunction; Natural Immunity; Pathogenesis; Pathway interactions; Phosphotransferases; Physiological; Process; Regulation; Research; Rest; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Stress; Structure; System; TNFSF11 gene; Testing; Tetracyclines; Transforming Growth Factor beta; Transgenic Mice; Transgenic Organisms; Tumor Necrosis Factor-alpha; Ventricular Remodeling; base; bone; caspase-8; cytokine; genetic approach; improved; in vivo; innovation; interstitial; member; mouse model; new therapeutic target; novel; novel strategies; overexpression; prevent; receptor; response; targeted treatment

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.

描述（由申请人提供）：介导心肌细胞生长、细胞死亡和病理重塑的信号网络的鉴定对于最终阐明心力衰竭的分子基础至关重要。长期目标是定义调节心脏重塑和心力衰竭的新型分子信号传导机制，并确定如何将它们用于治疗心肌疾病。本申请中的初步研究确定了一种新型 TAK1（TGFβ 激活激酶 1，也称为 MAP3K7）信号网络，该网络对于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对心脏病的影响很大程度上尚不清楚，其作用机制也不清楚。中心假设是，新型心脏保护性 TAK1 信号网络关键参与心肌细胞存活和正常心脏结构和功能的维持，从而防止病理性心脏重塑和心力衰竭进展。本申请的目的是通过使用综合分子、遗传和功能方法以及该研究团队开发的独特转基因小鼠，评估心脏中 TAK1 信号网络的生理功能及其在不良心脏重塑和衰竭发病机制中的作用。在强有力的初步数据的指导下，该假设将通过追求 3 个具体目标来检验：1）研究 TAK1 在调节体内心脏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塑和衰竭。 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塑中的作用。首先，将使用心脏特异性 TAK1 敲除小鼠来检查 TAK1 在调节心脏细胞存活和心肌稳态中的生理必要性。接下来，将在心力衰竭小鼠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，将使用分子和遗传学方法研究 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。这些研究将揭示新的机制观点，从这些观点可以治疗心力衰竭，并为药理学和基因靶向提供候选者。此外，拟议的研究将具有重要意义，因为在这里学到的知识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。