TRADD信号通路在心肌细胞程序性坏死所引起的心肌重构和心力衰竭中的作用及分子机制

细胞程序性坏死（Necroptosis）失调可导致心脏发育异常等疾病的发生。成体心脏中如何调控心肌Necroptosis确切分子机制尚未阐明。我们最新报道TAK1是其中关键分子。在TNFα死亡通路中，TRADD是TAK1上游分子，是TNFα受体结合蛋白。我们在普通小鼠慢性心衰模型中发现TAK1和TRADD表达显著升高。TRADD敲除成年小鼠心功能下降心室重构加剧，逐渐发展为心衰。在体外培养心肌细胞中低表达TRADD检测到RIP1-RIP3坏死小体。我们推测TRADD表达下调通过增强心肌Necroptosis而导致心肌细胞死亡，继而引发心室重构，最终导致心力衰竭。我们拟采用小鼠压力超负荷以及体外心肌细胞Necroptosis模型，观察TRADD表达变化对细胞死亡相关信号分子的影响，明确其在调控心肌Necroptosis中的分子机制和心衰中保护作用。此研究将为心衰发病机理提供新思路。

Programmed necrosis (necroptosis) plays an important role in development, tissue homeostasis, and disease pathogenesis. The molecular mechanisms that regulate necroptosis in the heart and its physiological relevance in myocardial remodeling and heart failure remain largely unknown. We identified an important role for TAK1 (transforming growth factor β–activated kinase 1) in regulating necroptotic myocyte death, myocardial remodeling, and heart failure propensity. TRADD (TNFRSF1A-associated via death domain) is an important signaling molecule that is located upstream of the TAK1.The physiological function of TRADD signaling in the heart and its role in the pathogenesis of heart disease is still largely unknown. . Importantly, we observed that both TRADD and its interacting partner, TAK1, were upregulated in mouse models of heart failure. We partially characterized the Traf2fl/fl-αMHC-Cre mice, which show cardiac dysfunction and pathological remodeling at 2 months. Inactivation of TRADD promotes necroptotic cell death in cardiomyocytes and promotes the RIP1-RIP3 necroptosis complex. Our preliminary studies reveal a previously unidentified, novel role for TRADD in regulating programmed necrosis and myocardial remodeling using cardiac-specific gene-targeted mice. . Our central hypothesis is that TRADD signaling is a nodal regulator of cardiac necroptosis, pathological remodeling and heart failure progression. Here we propose an investigation of the novel function of TRADD in regulating myocardial survival and heart failure propensity both in vivo and in vitro. We will implement a series of innovative genetic, molecular, and functional approaches to identify novel signaling mechanisms underlying cardiac remodeling and heart failure. The biology surrounding the TRADD signaling network is novel and innovative, and will likely uncover new mechanistic perspectives from which heart failure can be approached therapeutically, especially given our preliminary data suggesting a critical role for TRADD in cardiac cell survival and overall cardiac homeostasis.