As a post-doctoral research fellow, I have been working on several projects related to molecularsignaling mechanisms of cardiac hypertrophy and heart failure. My current projects investigate howprotein kinases such as apoptotic signal-regulating kinase 1 (ASK1) and TGF -activated kinase 1(TAK1) regulate the cardiomyocyte hypertrophic response and apoptosis. These efforts resultedpublications in Molecular Cellular Biology 2006 and Nature Cell Biology 2009 in press. Other researchprojects investigate different roles of protein kinase C (PKC) isoforms in the regulation of cardiaccontractility and heart failure propensity, and a manuscript is in revision at Circulation that reveal novelinsights into PKC signaling in the heart. The molecular mechanisms that underpin cardiachypertrophy and its culmination in heart failure is a highly active area of research in our field, andrecent work from us and others is revealing a more complicated network of signaling effectors thanoriginally anticipated. For example, my most recent studies show that TAK1 functions as a criticalcontrol point for the hypertrophic response through crosstalk with several other signaling pathwayssuch as calcineurin-NFAT, IKK-NF B, and MAPKs in cardiac myocytes. Here I hypothesize that TAK1serves as a central regulator of the hypertrophic signaling network in vivo, which will be investigatedusing 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 cardiachypertrophy in vivo. 2) To determine if activation of TAK1 is sufficient to induce cardiac hypertrophy inthe adult heart. 3) To define a potential signaling network between TAK1 and other hypertrophicsignaling pathways including calcineurin and NF B. This approach may suggest novel therapeuticstrategies if conclusive proof can be established in animal models implicating TAK1 signaling in thepathogenesis of hypertrophy and/or heart failure. During the first 1-2 years of the mentored phase ofthis award, I plan to obtain further research experience and knowledge using relevant research andeducational resources of the institution, finish up my current research projects, and obtain anindependent investigator position. My long term career goal is to establish an independent researchprogram with a focus on molecular mechanisms of cardiac hypertrophy and heart failure. During theindependent R00 phase of this award, I will invest most of my time and efforts in my proposed andother new research projects and prepare for subsequent grant support. With regard to researchenvironment, University of Cincinnati together with Children's Hospital provide outstandinginfrastructure and collaborators. In fact, the molecular cardiovascular group of scientists here arenationally recognized and highly interactive. The sponsor's laboratory is an ideal environment to fostermy career development in cardiovascular biology, with great mentorship. The two-phase careerdevelopment plan (both mentored and independent) fits well with my career goals and priorexperience, which will substantially enhance my research career and allow the pursuit of novelresearch directions and approaches.
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.
|Guo, Xiaoyun; Yin, Haifeng; Li, Lei et al. (2017) Cardioprotective Role of Tumor Necrosis Factor Receptor-Associated Factor 2 by Suppressing Apoptosis and Necroptosis. Circulation 136:729-742|
|Li, Lei; Li, Jing; Drum, Benjamin M et al. (2017) Loss of AKAP150 promotes pathological remodelling and heart failure propensity by disrupting calcium cycling and contractile reserve. Cardiovasc Res 113:147-159|
|Li, Lei; Guo, Xiaoyun; Chen, Yi et al. (2016) Assessment of Cardiac Morphological and Functional Changes in Mouse Model of Transverse Aortic Constriction by Echocardiographic Imaging. J Vis Exp :|
|Guo, Xiaoyun; Yin, Haifeng; Chen, Yi et al. (2016) TAK1 regulates caspase 8 activation and necroptotic signaling via multiple cell death checkpoints. Cell Death Dis 7:e2381|
|Li, Lei; Chen, Yi; Doan, Jessica et al. (2014) Transforming growth factor ?-activated kinase 1 signaling pathway critically regulates myocardial survival and remodeling. Circulation 130:2162-72|
|Liu, Qinghang; Chen, Yi; Auger-Messier, Mannix et al. (2012) Interaction between NF?B and NFAT coordinates cardiac hypertrophy and pathological remodeling. Circ Res 110:1077-86|