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

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.

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。

最近大量报道炎症引发的心肌死亡在心脏重构和心力衰竭中起的重要作用，而压力超负荷引起的心脏重构中的细胞死亡因为程序性坏死的研究报道很少，相关分子机制还不明了。我们通过本研究，初步明确TAK1调控心肌细胞程序性坏死在压力超负荷中所起的所起的作用及其分子机制，我们发现压力超负荷引起心脏局部和循环中的TNFα水平的升高，然后通过TRADD的表达上调，进而激活TAK1，引发RIP1-RIP3坏死小体的形成，从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。在实际课题进展过程中，我们也有了一些阶段性的发现和结论：（1）TRADD受体并不是如经典的通过TGF-β信号通路促进下游TAK1蛋白活化，从而引起纤维化生物学变化，进而导致压力超负荷下的心肌重构；而是通过程序性坏死凋亡途径-TNF-α1型受体（TNFRI）促进了心脏纤维化。（2）TAK1的激活除了招募caspase8，从而形成RIP1-RIP3坏死复合体外，还通过激活IKK-NFκB通路的活化，进而平衡心肌细胞的过度程序性坏死。（3）促心肌细胞存活信号通路NFκB的关键信号因子在TRADD调控心肌细胞程序性坏死中的起着重要的抑制作用。此项研究还将继续深入TRADD参与TNFα引起的IKK-NFκB信号通路中压力超负荷引起的心肌重构中发挥的重要作用和相关病理分子机制。截止目前，该项研究已经发表受本项目资助SCI论文5篇，培养硕士研究生3名，博士生1名。

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