髓样分化蛋白-2在动脉粥样硬化发生发展中介导炎症反应的作用机制和干预研究

动脉粥样硬化（AS）已经被认为是一个炎症反应的过程。在内毒素诱导的炎症反应中，Toll样受体4和髓样分化蛋白（MD）-2发挥着重要介导作用，MD-2是TLR4的辅助蛋白。虽然TLR4在AS中有着重要作用，但MD2是否也参与介导AS炎症反应尚无报道。我们前期工作发现一个通过靶向MD2而抗炎的小分子L6H9，可以抑制FFA与MD2的结合及其诱导的炎症反应，并在小鼠模型中显著缓解AS进程。基于此，我们假设：MD2在AS炎症反应中有着重要介导作用；MD2有望作为治疗AS的新靶点。本项目中，我们拟从分子、细胞和动物三个层面，深入阐明MD2介导ox-LDL、mm-LDL和FFA炎症反应的作用和机制，确证MD2在AS炎症反应发生发展中的调控机制；进一步利用AS临床样本，探讨MD2与AS临床进程的相关性。本项目预期发现MD2调控高脂- - 炎症- - AS的作用和机制，为防治AS提供新的治疗靶点。

Atherosclerosis (AS) has been considered as a chronic inflammation. TLR4 and MD2 play important roles in LPS-induced inflammation. MD2 is an assistant protein of LPS in transferring LPS inflammatory signaling pathway. Although TLR4 has been demonstrated as an important regulator in AS and AS-related inflammation, it is unclear whether MD2 is also involved in the hyperlipemia-induced AS-related inflammation. Our previous study found that a novel small molecule L6H9, which targets MD2 protein and inhibits LPS-induced inflammatory response, could inhibit FFA-MD2 binding and then FFA-induced inflammation. In AS mouse models, L6H9 also significantly attenuates AS development. Thus, we hypothesize that, MD2 plays an important role in mediating AS and AS-related inflammation and MD2 may be a new target for the treatment of AS. In this project, we plan to demonstrate the effects and mechanisms of MD2 in AS and AS-related inflammatory responses induced by ox-LDL, mm-LDL, and FFA, respectively, in the molecular, cellular, and animal levels. Further, we will perform the relevance study using clinical blood samples of AS patients. These studies will demonstrate the effects and mechanisms of MD2 protein regulating hyperlipemia- - -inflammation- - -AS pathway and provide the new therapeutic target for AS treatment.