隐球菌通过S100A10活化尿激酶-纤溶酶系统侵袭血脑屏障的机制研究

项目名称： 隐球菌通过S100A10活化尿激酶-纤溶酶系统侵袭血脑屏障的机制研究

项目编号： No.31470252

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 温海

作者单位： 中国人民解放军第二军医大学

项目金额： 86万元

中文摘要： 隐球菌引起的中枢神经系统感染严重危害着人类的健康，其与血脑屏障的关系可能是嗜中枢性的关键所在。研究表明，活化的纤溶酶系统有助于隐球菌通过血脑屏障，且另有研究表明纤溶酶系统的活化需要S100A10的参与。我们前期研究发现隐球菌可以上调内皮细胞S100A10的表达，这是否有助于隐球菌活化纤溶酶系统并侵袭血脑屏障仍未明确。本课题拟明确隐球菌上调脑微血管内皮细胞S100A10表达的病理生理意义。我们拟通过构建慢病毒载体沉默S100A10的表达，观察其对隐球菌通过血脑屏障的能力的影响,并观察沉默S100A10是否影响纤溶酶系统及基质金属蛋白酶的活化，进而影响隐球菌通过血脑屏障的能力。并进一步观察基质金属蛋白酶抑制剂对中枢神经系统隐球菌病的预防作用，为临床防治提供新的思路。

中文关键词： S100A10；新生隐球菌；尿激酶；纤溶酶；血脑屏障

英文摘要： Cryptococcus neoformans(C. n) is a medical fungus which badly damage huamn health by causing fatal meningoencephalitis,and the relationship between C.n and the blood-brain barrier(BBB) may be the key for C. n addicted to central nervous system(CNS).It's known that plasmin, urokinase activation contribute to the C.n travel across the BBB,and the plasminogen system activation requires the expression of S100A10 in tumor cells. Previously we found that C.n can upregulate the expression of S100A10 in endothelial cells, but the relationship between the increased expression of S100A10 and the ability of C.n travel across the BBB is unclear.We plan to investigate how can C.n upregulate S100A10 expression and its significance.We propose to confirm the up-regulation of S100A10 and urokinase by C.n，and construct the lentiviral vector which can silence S100A10, observing the ability of C.n travel across BBB composed of S100A10 silenced endothelial cells, and detect the activation of plasmin,urokinase and matrix metalloproteinases in the BBB system,verifing whether the silencing of S100A10 affect the ability of C.n travel across BBB by inhibiting plasmin and matrix metalloproteinases.Then we propose to observe the preventive effect of matrix metalloproteinase inhibitor on cryptococcosis, providing new ideas for clinical prevention and treatment of cryptococcosis.

英文关键词： S100A10;Cryptococcus neoformans;urokinase;plasmin;blood-brain barrier