Role of TAK1 Signaling Network in Cardiac Hypertrophy

TAK1 信号网络在心脏肥大中的作用

基本信息

批准号：
8432456
负责人：
Qinghang Liu
金额：
$ 23.7万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-04 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8432456
关键词：
Adult Age Animal Model Apoptosis Apoptotic Area Award Biological Biology Blood Circulation Calcineurin Cardiac Cardiac Myocytes Cardiovascular system Cell Death Cellular biology Data Development Development Plans Environment Failure Fostering Gene Targeting Genes Genetic Goals Grant Growth Heart Heart Diseases Heart Hypertrophy Heart failure Hypertrophy Institution Investigation Knockout Mice Knowledge Laboratories MAP Kinase Gene MAPK14 gene MAPK8 gene Manuscripts Mediating Membrane Mentored Clinical Scientist Development Award (K08)Mentors Mentorship Molecular Molecular and Cellular Biology Mus Muscle Cells Myocardium NFAT Pathway Nature Neonatal Nodal Pathogenesis Pathway interactions Pediatric Hospitals Phase Phosphotransferases Physiological Play Positioning Attribute Postdoctoral Fellow Process Protein Isoforms Protein Kinase Protein Kinase C Publications Publishing Regulation Research Research Infrastructure Research Personnel Research Project Grants Resources Rest Role Scientist Signal Pathway Signal Transduction Signaling Molecule Stimulus Stress Tetracyclines Time Transgenic Mice Transgenic Organisms Uncertainty Universities Work base career career development cell type design experience in vivo insight loss of function mouse model neonate novel novel strategies novel therapeutics overexpression programs receptor binding response

项目摘要

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.

项目摘要作为博士后研究员，我一直在研究与分子有关的几个项目心脏肥大和心力衰竭的信号传导机制。我目前的项目调查了如何蛋白激酶，例如凋亡信号调节激酶1（ASK1）和TGF®激活激酶1 （TAK1）调节心肌细胞肥大反应和凋亡。这些努力产生了分子细胞生物学的出版物2006和自然细胞生物学2009年的出版物。其他研究项目研究蛋白激酶C（PKC）同工型在心脏调节中的不同作用收缩性和心力衰竭的承诺，手稿正在流通上的修订中，揭示了新颖的深入了解心脏中的PKC信号。基础心脏的分子机制肥大及其在心力衰竭方面的高潮是我们领域的一个高度活跃的研究领域，我们和其他人的最新工作揭示了比较复杂的信号效应网络最初是预料的。例如，我最近的研究表明，tak1起着关键的作用与其他几个信号通路通过串扰的肥厚反应的控制点例如钙调蛋白-NFAT，IKK-NF¿B和心肌细胞中的MAPK。在这里我假设tak1 作为体内肥厚信号网络的中央调节剂，将研究该网络使用心脏特异性TAK1转基因和基因靶向小鼠模型。为了检查假设，提出了三个具体目标：1）确定tak1的遗传缺失是否会减少心脏体内肥大。 2）确定tak1的激活是否足以诱导心脏肥大成人心。 3）定义tak1和其他肥厚型之间的潜在信号网络信号通路在内策略是否可以在动物模型中建立明确的证据，隐含在肥大和/或心力衰竭的发病机理。在修补阶段的头1-2年中该奖项，我计划使用相关研究获得进一步的研究经验和知识，该机构的教育资源，完成我当前的研究项目，并获得独立研究者职位。我的长期职业目标是建立独立研究计划着重于心脏肥大和心力衰竭的分子机制。在该奖项的独立R00阶段，我将大部分时间和精力投入到我的建议和其他新的研究项目，并为随后的赠款支持做准备。关于研究辛辛那提大学环境以及儿童医院提供出色的基础架构和合作者。实际上，这里的分子心血管群是全国认可和高度互动。赞助商的实验室是培养的理想环境我在心血管生物学方面的职业发展，具有良好的心态。两相职业发展计划（指导和独立）非常适合我的职业目标和事先经验，这将大大改善我的研究职业并允许追求新颖研究方向和方法。