新生儿细菌性脑膜炎是儿科严重的感染性疾病之一,尽管抗生素用于临床治疗已60多年之久,但患儿病死率仍得不到明显的改善，究其原因是对其病理过程的研究还远远不够全面。大肠杆菌是导致新生儿脑膜炎最常见的革兰氏阴性致病菌。我们的前期研究证明尼古丁等环境因素可以通过重要炎症调节因子alpha7 nAChR介导的钙通道信号转导作用间接增强大肠杆菌的脑膜炎致病性。我们目前的研究证明钙信号转导是FimH与其受体CD48介导细菌及白细胞穿过血脑屏障所必需,但其分子机制并未完全明了。因此，本项目拟采用基因过表达与基因敲低及敲除技术探讨FimH与其受体CD48是如何通过钙信号转导发挥其致病作用，并观察基因过表过或缺失对FimH介导钙信号转导和菌体黏附及侵袭能力的影响。因此,该项目将依据体内及体外实验结果，探明钙信号转导与大肠杆菌脑膜炎病理过程及其发病机制的关系.其预期结果对该病的防治有着非常重要的理论及临床意义。

Despite advances in antimicrobial chemotherapy, the morbidity and mortality associated with neonatal bacterial meningitis have remained significant. This is due to our incomplete understanding of the pathogenesis and pathophysiology of this serious disease. Escherichia coli K1 is the most common gram-negative bacterium that causes meningitis during the neonatal period. we have previously shown that nicotine was able to enhance meningitic Ecoli K1 invasion of human brain microvascular endothelial cell(BMEC) though calcium signaling pathway mediated by a7 nAchR . we present study indicated that calcium signaling medatedd by type 1 fimbrial-FimH and its receptor CD48 is essential for bacterial and neutrophil migration across BMEC,the pathogenic mechanisms are largely unknown. In order to dissect the role of FimH and CD48 in E. coli adhesion and invasion ,a deletion mutant (ΔFimH-E44：22A33) will be made from meningitic E.coli K1 strain E44.Tissue culture expriments using HBMEC and the neonatal mouse meningitic model will be established to identificate the pathogenesis and pathophysiology mediated by FimH.