Role of TAK1 Signaling Network in Cardiac Hypertrophy

项目摘要 作为一名博士后研究员，我一直从事与分子相关的几个项目 心肌肥厚和心力衰竭的信号机制。我目前的项目调查如何 凋亡信号调节激酶1(ASK1)和转化生长因子活化蛋白激酶1等蛋白激酶 (TAK1)调节心肌细胞肥大反应和细胞凋亡。这些努力导致了 2006年《分子细胞生物学》和2009年《自然细胞生物学》出版。其他研究 项目研究了蛋白激酶C(PKC)亚型在心脏调节中的不同作用。 收缩能力和心力衰竭倾向，循环杂志正在修改一份手稿，揭示了一部小说 对心脏中PKC信号的洞察。心脏疾病的分子机制 肥厚及其导致心力衰竭是我们这个领域非常活跃的研究领域，并且 我们和其他人最近的研究揭示了一个更复杂的信号效应器网络 原本就在预料之中。例如，我最近的研究表明，TAK1发挥着关键的作用 肥大反应的控制点通过与其他几个信号通路的串扰 如钙调神经磷酸酶-NFAT、IKK-NFB和心肌细胞MAPKs。在这里，我假设TAK1 作为体内肥大信号网络的中央调节器，这将被研究 采用心脏特异性TAK1转基因和基因靶向小鼠模型。为了检验这一假设， 提出了三个具体目标：1)确定TAK1基因缺失是否会降低心脏 活体肥大。2)确定TAK1的激活是否足以诱导心肌肥厚。 成人的心脏。3)确定TAK1和其他肥厚性疾病之间的潜在信号网络 信号通路包括钙调神经磷酸酶和核因子B。这一途径可能提示新的治疗方法 策略，如果确凿的证据可以在动物模型中建立牵连TAK1信号在 肥厚和/或心力衰竭的发病机制。在指导阶段的前1-2年内 此次获奖，我计划利用相关研究和研究获得更多的研究经验和知识 机构的教育资源，完成我目前的研究项目，并获得 独立调查员职位。我的长期职业目标是建立一个独立的研究机构 重点研究心肌肥厚和心力衰竭的分子机制。在.期间 独立R00阶段的这个奖项，我会把我的大部分时间和努力投入到我提出的和 其他新的研究项目，并为随后的赠款支持做好准备。关于研究 环境，辛辛那提大学与儿童医院一起提供杰出的 基础设施和合作者。事实上，这里的分子心血管科学家小组是 国家认可，互动性强。赞助商的实验室是培养人才的理想环境 我在心血管生物学方面的职业发展，得到了很好的指导。两个阶段的职业生涯 发展计划(包括有指导的和独立的)非常符合我的职业目标和职业经历 经验，这将极大地促进我的研究事业，并允许我追求小说 研究方向和方法。

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 TGF¿-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.