急性高眼压介导视网膜Müller细胞AQP4内化／降解及其信号转导

项目名称： 急性高眼压介导视网膜Müller细胞AQP4内化／降解及其信号转导

项目编号： No.31300911

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 甘胜伟

作者单位： 重庆医科大学

项目金额： 25万元

中文摘要： 水通道蛋白4（AQP4）是视网膜内含量最多、分布最广的水通道蛋白，呈极性分布于Müller细胞特殊膜域，与视网膜水电解质运输平衡及视觉活动调节有联系。AQP4的极性分布与laminin等锚定蛋白有关。课题组发现急性高眼压可导致AQP4内化（internalization，即AQP4进入内涵体）及分选至溶酶体，并伴随其水转运功能的降低，压力/缺血缺氧可能参与该过程；外源性laminin可影响加压时AQP4的内化，提示AQP4内化可能与锚定蛋白有关。文献证实，某些蛋白激酶的激活也可导致AQP4内化。然而，压力/缺血缺氧介导AQP4内化/降解的规律及其信号通路尚不明确。为此，本研究将应用分子生物学等方法，从在体模型和加压/氧-糖剥夺培养Müller细胞中研究AQP4锚定蛋白与其内化的关系及蛋白激酶活性改变对AQP4内化及水肿的影响，以阐明高眼压介导视网膜损伤的分子机制，并为新药开发提供实验基础。

中文关键词： 水通道蛋白4；胶质细胞；水肿；内化；溶酶体降解

英文摘要： Aquaporin-4(AQP4) is the predominant aquaporins and abundantly expressed in retina with a polarized pattern targeted to specific membrane domains of Müller cells，which plays important roles in the water and ion balance and the regulation of visual function. It is reported that the anchoring proteins of AQP4, such as laminin and agrin, are responsible for the polarized expression of AQP4 in the Müller cells. The preliminary experiments in our study initially provided the evidences that AQP4 was internalized into early and late endosome in the retinae induced by acute ocular hypertension, and followed by its sorting to lysosome for degradation, accompanying by the downregulation of water transport, which suggested that internalization of retinal glial AQP4 can be induced by hydrostatic pressure and/or hypoxia-ischemia；In vivo study showed exogenous laminin, one of extracellular matrix molecules, can affect the occurrence of AQP4 internalization induced by hydrostatic pressure, which suggested AQP4 internalization may be related to its anchoring mechanism. Some studies showed the activation of several protein kinases also can result in AQP4 internalization. However, the details of AQP4 internalization followed by its lysosomal degradation induced by hydrostatic pressure and/or hypoxia-Ischemia and the potential sig

英文关键词： Aquoprin-4；Glial cells；Edema；Internalization；lysosomal degradation