Role of TAK1 Signaling Network in Cardiac Hypertrophy

作为一名博士后研究员，我一直在从事与心脏肥大和心力衰竭的分子信号机制相关的几个项目。我目前的项目研究如何蛋白激酶，如凋亡信号调节激酶1（ASK 1）和TGF 2激活激酶1（TAK 1）调节心肌细胞肥大反应和凋亡。这些努力导致出版物在分子细胞生物学2006年和自然细胞生物学2009年出版。其他研究项目调查了蛋白激酶C（PKC）亚型在调节心肌收缩力和心力衰竭倾向中的不同作用，Circulation正在修订一份手稿，揭示了心脏中PKC信号传导的新见解。支持心脏肥大及其在心力衰竭中达到顶峰的分子机制是我们领域的一个高度活跃的研究领域，我们和其他人最近的工作揭示了一个比最初预期更复杂的信号效应器网络。例如，我最近的研究表明，TAK 1通过与其他几种信号通路如心肌细胞中的钙调神经磷酸酶-NFAT、IKK-NF：B和MAPK的串扰，作为肥大反应的关键控制点发挥作用。在这里，我假设，TAK 1作为一个中央调节器的肥大信号网络在体内，这将是研究使用心脏特异性TAK 1转基因和基因靶向小鼠模型。为了验证这一假设，提出了三个具体目标：1）确定TAK 1基因缺失是否减少体内心脏肥大。2)确定TAK 1的激活是否足以诱导成人心脏的心肌肥大。3)明确TAK 1与其他肥大信号通路包括钙调神经磷酸酶和NF：B之间的潜在信号网络。如果在动物模型中建立了TAK 1信号转导参与肥大和/或心力衰竭发病机制的确凿证据，这种方法可能会提出新的治疗策略。在该奖项的指导阶段的前1-2年，我计划利用该机构的相关研究和教育资源获得进一步的研究经验和知识，完成我目前的研究项目，并获得独立研究员职位。我的长期职业目标是建立一个独立的研究计划，重点是心脏肥大和心力衰竭的分子机制。在这个奖项的独立R 00阶段，我将投入我的大部分时间和精力在我的建议和其他新的研究项目，并准备后续的赠款支持。在研究环境方面，辛辛那提大学和儿童医院提供了出色的基础设施和合作者。事实上，分子心血管组的科学家在这里是全国公认的和高度互动的。赞助商的实验室是一个理想的环境，以促进我在心血管生物学的职业发展，与伟大的导师。两阶段的职业发展计划（包括指导和独立）非常符合我的职业目标和先前的经验，这将大大提高我的研究生涯，并允许追求新的研究方向和方法。 公共卫生相关性：更好地表征信号机制对于可能设计治疗肥厚性心脏病的新方法至关重要。在这里，我们将评估如何TAK 1信号调节心脏肥大使用基因操纵的小鼠模型。如果在动物模型中建立确凿的证据，表明TAK 1信号转导是肥大和/或心力衰竭的关键调节因子，则这种方法可能提出新的治疗策略。

DESCRIPTION (provided by applicant): Project Summary As a post-doctoral research fellow, I have been working on several projects related to molecular signaling mechanisms of cardiac hypertrophy and heart failure. My current projects investigate how protein kinases such as apoptotic signal-regulating kinase 1 (ASK1) and TGF2-activated kinase 1 (TAK1) regulate the cardiomyocyte hypertrophic response and apoptosis. These efforts resulted publications in Molecular Cellular Biology 2006 and Nature Cell Biology 2009 in press. Other research projects investigate different roles of protein kinase C (PKC) isoforms in the regulation of cardiac contractility and heart failure propensity, and a manuscript is in revision at Circulation that reveal novel insights into PKC signaling in the heart. The molecular mechanisms that underpin cardiac hypertrophy and its culmination in heart failure is a highly active area of research in our field, and recent work from us and others is revealing a more complicated network of signaling effectors than originally anticipated. For example, my most recent studies show that TAK1 functions as a critical control point for the hypertrophic response through crosstalk with several other signaling pathways such as calcineurin-NFAT, IKK-NF:B, and MAPKs in cardiac myocytes. Here I hypothesize that TAK1 serves as a central regulator of the hypertrophic signaling network in vivo, which will be investigated using cardiac specific TAK1 transgenic and gene targeted mouse models. To examine the hypothesis, three specific aims are proposed: 1) To determine if genetic deletion of TAK1 reduces cardiac hypertrophy in vivo. 2) To determine if activation of TAK1 is sufficient to induce cardiac hypertrophy in the adult heart. 3) To define a potential signaling network between TAK1 and other hypertrophic signaling pathways including calcineurin and NF:B. This approach may suggest novel therapeutic strategies if conclusive proof can be established in animal models implicating TAK1 signaling in the pathogenesis of hypertrophy and/or heart failure. During the first 1-2 years of the mentored phase of this award, I plan to obtain further research experience and knowledge using relevant research and educational resources of the institution, finish up my current research projects, and obtain an independent investigator position. My long term career goal is to establish an independent research program with a focus on molecular mechanisms of cardiac hypertrophy and heart failure. During the independent R00 phase of this award, I will invest most of my time and efforts in my proposed and other new research projects and prepare for subsequent grant support. With regard to research environment, University of Cincinnati together with Children's Hospital provide outstanding infrastructure and collaborators. In fact, the molecular cardiovascular group of scientists here are nationally recognized and highly interactive. The sponsor's laboratory is an ideal environment to foster my career development in cardiovascular biology, with great mentorship. The two-phase career development plan (both mentored and independent) fits well with my career goals and prior experience, which will substantially enhance my research career and allow the pursuit of novel research directions and approaches. PUBLIC HEALTH RELEVANCE: Project Narrative A better characterization of signaling mechanisms is critical for possibly designing novel approaches for treatment of hypertrophic heart diseases. Here we will evaluate how TAK1 signaling regulates cardiac hypertrophy using genetically manipulated mouse models. This approach may suggest novel therapeutic strategies if conclusive proof can be established in animal models implicating TAK1 signaling as a key regulator of hypertrophy and/or heart failure.