核孤儿受体TR3抑制炎症的分子机制和信号通路

Inflammatory response is a "double-edged sword". Appropriate inflammatory response helps to removal of pathogens; however, aggressive inflammatory response may lead to multi-organ dysfunction and even death. Therefore, studying the precise regulatory mechanism for inflammatory response is the key to solve many inflammation-related diseases. TR3, encoded by immediate early gene NR4A1, is a nuclear orphan receptor, and plays important roles in cell growth, proliferation and apoptosis in response to different stimuli. It has been reported that TR3 may participate in the regulation of inflammation, but the exactly regulatory mechanism remain elusive. In our recent preliminary experiments, we found that TR3 knock-out mice are much more sensitive to the LPS-induced endotoxin shock than wild-type mice. TR3 can bind to NF-κB, an important factor in inflammation, and inhibits its activity. Moreover, we found that protein kinase p38 mediates the phosphorylation of TR3 upon LPS stimulation. In current application, we will study the molecular mechanism and signal transduction pathway for the inhibitory effect of TR3 on inflammation, clarify functions of p38-mediated TR3 phosphorylation on inflammation, and screen TR3-targeted anti-inflammatory drugs. Thus, our study will help to reveal the mechanism for inflammation, and contribute to the prevention and control of inflammation-related diseases.

机体的炎症反应是一把"双刃剑"。适当的炎症反应有利于机体对外界病原体的清除，过激的炎症反应则可能导致机体多器官功能紊乱甚至死亡。因此，研究机体对炎症反应的精确调控机制是解决众多炎症相关疾病的关键。TR3是由立早基因NR4A1编码的核受体，在不同的外界刺激下，它可调控细胞生长，增殖以及凋亡等过程。有文献报道，TR3可能参与了对炎症反应的调控。然而，TR3调控炎症的具体机制仍不清楚。在预实验中，我们发现TR3敲除的小鼠对LPS诱导的内毒素休克比野生型小鼠更为敏感。TR3可以与炎症反应的重要因子NF-κB结合，并抑制其活性。同时，我们发现在LPS处理下，p38可以诱导TR3磷酸化修饰。在本课题中，我们将研究TR3负调控炎症反应的分子机理，阐明p38诱导的磷酸化对TR3抗炎功能的影响，并筛选以TR3为靶点的抗炎药物。通过研究，将为揭示炎症发生发展机制、控制和预防炎症相关疾病提供理论依据。

本项目研究了核受体TR3抑制炎症的分子机制与信号通路，初步阐明了TR3通过与p65的相互作用，抑制p65与DNA的结合，从而抑制NF-kB的转录激活活性，最终抑制LPS引起的炎症反应的机制。在此基础上我们筛选到一个以TR3为靶点的抗炎小分子化合物，并申请了专利。此外，本项目还研究了TR3参与调控细胞自噬性死亡的机制。研究表明，在小分子药物THPN处理下，TR3通过与Nix相互作用可定位于线粒体。随后TR3在Tom20的辅助下与线粒体内膜蛋白Ant1结合，从而使得线粒体膜电位丧失，促进线粒体自噬的发生。过量的线粒体自噬则使得细胞发生自噬性死亡。该研究初步阐明了TR3调控线粒体自噬的机制，为进一步寻找通过自噬调控炎症的药物提供了一定的理论依据。