miR-155、miR-192调控Rho A/Rho GTPase信号通路对原发性开角型青光眼的干预

项目名称： miR-155、miR-192调控Rho A/Rho GTPase信号通路对原发性开角型青光眼的干预

项目编号： No.81470633

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王峰

作者单位： 哈尔滨医科大学

项目金额： 67万元

中文摘要： 结缔组织生长因子（CTGF）上调和小梁网细胞外间质沉积是原发性开角型青光眼主要发病机制；miR155和miR192是调控细胞外间质表达的重要基因。我们证实miR192抑制物可减少小梁网细胞外间质表达，发现CTGF诱导小梁网细胞中miR155表达明显增加，但其机制有待探讨。我们提出假说miR155可能调控小梁网细胞外间质表达，导致小梁网组织结构和功能变化。为验证这一假说，将采用腺病毒转染、微流体三维细胞培养、基于流体力学的眼前节灌注等手段，从分子、细胞以及动物整体水平等方面，对比研究miR-155、miR-192对小梁网细胞CTGF、Neuromedin U、细胞外间质蛋白表达的影响，及对小梁网、Schlemm管等结构的影响，探讨miR155对信号通路RhoA/Rho GTPase的调控。本研究将从miR-155这个新视点为揭示原发性开角型青光眼的调控机制奠定基础，为治疗青光眼提供新的思路。

中文关键词： 原发性开角型青光眼；流体力学；小梁网；三维体外培养；微小RNA

英文摘要： Glaucoma is a common blinding disease worldwide and is frequently associated with elevated intraocular pressure (IOP) caused by increased resistance to aqueous humor outflow through the trabecular meshwork (TM). Upregulation of CTGF and extracellular matrix (ECM) deposits in TM is main molecular change of primary open angle glaucoma (POAG). Research confirmed that both miR155 and miR192 can regulate increase of expression of ECM which leads to renal fibrosis. Our result confirmed that miR192 inhibitor can decrease expression of ECM in TM cells. Our previous result also indicated that expression of miR155 increase significantly in TM cell transfected with Ad-CTGF. We suppose that miR155 play important role in the regulation of ECM expression in TM of POAG. To confirm the hypothesis, we will comparison between miR155 and miR192 on expression of CTGF, neuromedin U, ECM and morphological change of TM and Schlemm' canal which was based on Ad transfection, cultured TM cells with three dimension microfluidic technique, anterior segmental perfusion of tracer based on fluid dynamics by using rat primary TM cells and CTGF conducted POAG model through molecular, cell and whole model level. We also explore the target gene of miR155 on the RhoA/Rho GTPase signaling pathway which is downscream of CTGF. The completion of these specific aims should provide new insights into the molecular mechanism involving in the regulation relevant to the maintenance of normal levels of intraocular pressure in the eye and the pathogenesis of the TM in the glaucoma. This information should be useful in identifying novel targets for therapeutic approaches aimed at delaying or preventing the abnormal elevation of intraocular pressure, which constitutes the best-characterized risk factor of delevoping glaucoma.

英文关键词： primary open angle glaucoma;fluid dynamics;trabecular meshwork;culture with three dimension technique;microRNA