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

基本信息

批准号：
9187491
负责人：
Qinghang Liu
金额：
$ 38.63万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-17 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9187491
关键词：
Address Adult Apoptosis Biological Process Bone Morphogenetic Proteins Bypass CASP8 gene 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 Heart Heart Diseases Heart Hypertrophy Heart failure Homeostasis Human Hypertrophy Immune Cell Activation In Vitro Inflammation Inflammatory Interleukin-1 Interleukin-18 Knockout Mice Knowledge MAP Kinase Gene MAP3K7 gene Maintenance Mediating Membrane Mission Mitogen-Activated Protein Kinases Modeling Molecular Molecular Genetics Mus Muscle Cells Myocardial Myocardial dysfunction Myocardium Natural Immunity Pathogenesis Pathologic Pathway interactions Pharmacology Phosphotransferases Physiological Process RIPK1 gene Regulation Research Rest Role Signal Pathway Signal Transduction Signaling Molecule Stress Structure System TNF gene TNFSF11 gene Testing Tetracyclines Therapeutic Transforming Growth Factor beta Transgenic Mice Transgenic Organisms United States National Institutes of Health Ventricular Remodeling base cytokine genetic approach human disease improved in vivo innovation interstitial member mouse model new therapeutic target novel novel strategies overexpression prevent public health relevance receptor response targeted treatment

项目摘要

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（通过应用提供）：介导心肌细胞生长，细胞死亡和病理重塑的信号网络的识别对于最终阐明心力衰竭分子基础至关重要。长期目标是定义调节和心力衰竭的新型分子信号传导机制，并确定如何将它们靶向用于心肌疾病。本应用程序中的初步研究确定了一种新颖的TAK1（TGFß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在心脏病中的意义在很大程度上尚不清楚，也不理解作用机理。中心假设是，新颖的心脏保护性TAK1信号网络与心肌细胞的存活至关重要，并维持正常的心脏结构和功能，从而防止病理心脏重塑和心力衰竭进展。该应用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唯一修改的小鼠，评估心脏中TAK1信号网络的生理功能及其在心脏不良重塑和失败的发病机理中的作用。在强大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在控制心脏细胞存活和体内心肌稳态中的基本作用。 2）确定tak1的激活是否足以保护心脏免受不良重塑和通过促进细胞存活而衰竭。 3）确定TAK1依赖性心脏保护基础的分子机制及其在控制心脏细胞死亡和心肌重塑中的作用。首先，将使用心脏特异性的TAK1基因敲除小鼠检查心脏细胞存活和心肌稳态的TAK1必要的生理学。接下来，将在心力衰竭的小鼠模型中评估四环素诱导的转基因表达的心脏保护潜力。最后，将使用分子和遗传方法研究TAK1介导的心脏保护的基础机制及其与其他细胞死亡/存活信号通路的潜在串扰。这些研究将揭示可从治疗方法接近心力衰竭的新机械观点，并为药物和遗传靶向提供候选者。此外，拟议的研究将具有重要意义，因为这里学到的知识也将有助于改善对其他细胞系统和疾病模型中细胞存活和稳态调节的了解。