Role of TAK1 Signaling Network in Cardiac Hypertrophy

项目简介（由申请人提供）：项目概述作为博士后，我一直从事多个与心脏肥厚和心力衰竭分子信号机制相关的项目。我目前的项目研究蛋白激酶如凋亡信号调节激酶1 （ASK1）和tgf2活化激酶1 （TAK1）如何调节心肌细胞肥厚反应和凋亡。这些成果发表在《分子细胞生物学2006》和《自然细胞生物学2009》上。其他研究项目调查了蛋白激酶C （PKC）异构体在心脏收缩性和心力衰竭倾向调节中的不同作用，《循环》杂志上的一篇手稿正在修订中，该手稿揭示了心脏中PKC信号传导的新见解。心脏肥厚及其在心力衰竭中达到顶峰的分子机制是我们这个领域一个非常活跃的研究领域，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网络。例如，我最近的研究表明，TAK1通过与心肌细胞中钙调磷酸酶- nfat、IKK-NF:B和MAPKs等其他信号通路的串音，作为肥厚反应的关键控制点发挥作用。在这里，我假设TAK1在体内作为肥厚信号网络的中心调节器，这将通过心脏特异性TAK1转基因和基因靶向小鼠模型进行研究。为了验证这一假设，提出了三个具体目标：1)确定TAK1基因缺失是否会减少体内心脏肥厚。2)确定TAK1的激活是否足以诱导成人心脏肥厚。3)确定TAK1与钙调磷酸酶和NF:B等其他肥厚性信号通路之间的潜在信号网络。如果能在动物模型中建立明确的证据，表明TAK1信号在肥厚和/或心力衰竭的发病机制中起作用，这种方法可能会提出新的治疗策略。在该奖项指导阶段的前1-2年，我计划利用学校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，并获得独立研究者的职位。我的长期职业目标是建立一个独立的研究项目，重点研究心脏肥厚和心力衰竭的分子机制。在这个奖项的独立R00阶段，我将把我的大部分时间和精力投入到我提出的和其他新的研究项目中，并为随后的资助支持做准备。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，这里的分子心血管科学家团队是全国公认的，并且高度互动。主办方的实验室是一个理想的环境，可以促进我在心血管生物学方面的职业发展，并有很好的指导。两阶段的职业发展规划（指导和独立）与我的职业目标和之前的经验非常吻合，这将大大提升我的研究生涯，并使我能够追求新的研究方向和方法。

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.