RAGE-TLR4新型异二聚体参与MCD癫痫发病机制的研究

皮质发育障碍（MCD）内过度放大的炎症反应是癫痫发生的重要原因。我们的前期研究发现晚期糖基化终末产物受体（RAGE）介导了MCD内的炎症放大效应，且与Toll样受体（TLR）协同诱导炎症反应，但具体机制不清。已有证据提示RAGE和TLR可形成异二聚体而放大炎症效应，因此针对预实验中发现的RAGE-TLR4新型异二聚体现象，我们认为RAGE与TLR4形成异二聚体放大了MCD炎症反应，并诱导癫痫的发生。本项目拟在MCD动物模型、MCD胶质细胞和手术标本中验证RAGE-TLR4异二聚体的表达和分布，研究其与配体的识别模式，在体外构建RAGE-TLR4异二聚体表达体系，增强或抑制RAGE-TLR4异二聚体信号后观察MCD炎性通路的改变及其与癫痫发生的关系。RAGE-TLR4异二聚体作为一种新的炎症放大形式，本课题将深入研究其在MCD炎症反应和癫痫发生中的作用及其机制，为阐释MCD致痫过程提供证据。

Excessive inflammation existed in malformation of cortical development(MCD) is a important cause of MCD-related epilepsy. Our previous study indicated that advanced glycation end products receptor(RAGE)play a important role in exacerbating of MCD inflammation in coordination with Toll-like receptor(TLR), but the details are unclear. Base on the evidences that RAGE-TLR heterodimer can mediate the inlargement of inflammation, as well as the specific RAGE-TLR4 heterodimer existed in our preliminary research, we had a hypothesis that new heterodimer of RAGE-TLR4 mediated the inflammation exacerbating in MCD and induced the seizure.To explore the detailed roles of RAGE-TLR4 heterodimer, this project will detect the temporal and spatial pattern of RAGE-TLR4 heterodimer in MCD animal model, glial culture and surgical samples.The recognition of HMGB1 with this heterodimer will also be explored.The downstream change of inflammation will be focused after RAGE-TLR4 heterodimer intervention(enhancement and interruption), as well as the epileptogensis of these inflammation cytokines, TRIF signal and RAGE-TLR4 heterodimer. Overall, this study will explore the role of new RAGE-TLR4 heterodimer in inflammation exacerbation and MCD epileptogensis, and find possible targets to treat MCD related epilepsy through blocking RAGE-TLR4 heterodimer.