以细菌感染宿主的重要信号通路为靶点是目前抗感染治疗的研究前沿。前期研究中，我们发现以α7 nAChR为靶点能有效防治新生小鼠大肠杆菌（E. coli）脑膜炎，但E. coli如何激活α7 nAChR介导脑膜炎的发生和发展仍未阐明。最近，我们研究发现E. coli可诱导α7 nAChR内源性配体SLURP1的分泌，并初步证明SLURP1可通过α7 nAChR促进E. coli的侵袭和白细胞迁移。据此，我们提出诱导SLURP1分泌是E. coli激活α7 nAChR并介导脑膜炎发生和发展关键环节的研究假说。本项目拟利用过表达和敲除SLURP1等手段，E. coli脑膜炎模型、α7 nAChR敲除小鼠、激酶抑制剂等工具，阐明SLURP1-α 7nAChR在E. coli脑膜炎发生和发展中的关键作用及其分子机制，为明确以α7 nAChR为靶点防治新生儿E. coli K1脑膜炎的机理提供研究基础。

Recently, the concept of host-directed antimicrobial drugs against pathogens has received widespread attention in the scientific community. Our previous studies have shown that memantine, an α7 nAChR antagonist, could efficiently block neonatal Escherichia coli (E. coli) meningitis. However, the exact mechanisms by which α7 nAChR contribute to the neonatal E. coli meningitis remain unknown. Recently, in our preliminary study, it was shown that E. coli could enhance the expression of SLURP1, an endogenous ligand of a7 nAChR. We also found that SLURP1 could promote E. coli-induced invasion of brain microvascular endothelial cell and polymorphonuclear neutrophil transmigration. Therefore, we hypothesize that enhancement in the expression of SLURP1 could represent the underlying mechanism to explain the contribution of α7 nAChR to neonatal E. coli meningitis. In this proposal, we will dissect this underlying mechanism of SLURP1-α7 nAChR using gene editing technique, cell and animal models, α7 nAChR knockout mice, kinase inhibitors and so on. The completion of this project will provide novel evidence into the development of α7 nAChR antagonists in the prevention and treatment of neonatal E. coli meningitis.