尿素作为一种新的DAMP激活神经免疫加重脑缺血损伤的机制研究

脑缺血后神经组织坏死释放的DNA、S100蛋白、腺苷等内源性损伤相关分子模式（DAMP），通过Toll样受体等模式识别受体（PRR）激活星形胶质细胞（AS），引发炎症反应，加重脑缺血损伤。我们前期获得尿素参与脑缺血损伤的初步证据：小鼠脑缺血组织中尿素含量显著增多；脑损伤体积与尿素含量呈正相关；体外证实尿素能够促进AS增殖和炎症介质（CCL2、IP-10、IFN-γ）的表达。由此我们推测：脑缺血过程中，尿素作为危险预警分子-DAMP被AS的PRR识别，通过TLR4/TRAF6/NF-κB通路促进AS活化；活化的AS释放炎症介质趋化巨噬细胞和NK细胞等外周炎症细胞进入脑内，进而加重脑损伤这一假说。我们拟从动物整体、细胞和分子水平开展研究，探讨尿素对AS增殖、活化作用机制及其加重脑损伤机制。研究结果对深入理解DAMP在脑缺血发生发展中的作用，为探索尿素循环作为脑缺血新的治疗靶点提供新的理论依据。

After cerebral ischemia, DNA, S100 protein, adenosine and other endogenous damage-associated molecular patterns(DAMPs) released by ischemic brain nervous tissue, can activate astrocytes (AS) through Toll like receptor and other pattern recognition receptors (PRR), trigger inflammatory response and aggravate cerebral ischemia injury. We obtained the preliminary evidence that urea was involved in cerebral ischemia injury in early stage: The content of urea in cerebral ischemic tissue of mice increased significantly; The volume of brain injury was positively correlated with the content of urea; In vitro, we have confirmed that urea could promote the astrocytes proliferation and express inflammatory mediators (CCL2, IP-10, IFN-γ). Therefore, we speculate that: During the process of cerebral ischemia, urea, as a risk early warning DAMP molecule, is recognized by PRR of astrocytes, and promotes activation of astrocytes through TLR4/TRAF6/NF-κB pathway; Activated astrocytes releases inflammatory and chemotactic mediators, attract macrophages, NK cells and other peripheral inflammatory cells into the brain, and then aggravating brain damage. We intend to study the effects of urea on the proliferation and activation of astrocytes and the mechanism of aggravating brain injury at in vivo, cellular and molecular level. This result provide a new theoretical basis for further understanding the role of DAMPs in the development of cerebral ischemia, and will be a new therapeutic target for exploring the mechanism of urea cycle in cerebral ischemia.