CADHERIN DYNAMICS AND GLAUCOMA

最近的临床试验表明，患有糖尿病的人显著、持续地降低眼压 青光眼会减缓或停止视力丧失，即使是在低眼压性青光眼患者中也是如此。同时网站的数量增加 青光眼的耐药性可能位于常规的引流途径，即细胞机制 产生这种额外阻力的原因尚不清楚。以前的工作指出了两种可能性 并不是相互排斥的：(I)细胞外基质材料的异常堆积和/或改变 或(Ii)细胞间连接功能的改变(和相关的 Schlemm管内壁的边缘孔)。 在目前的应用中，我们建议研究一族细胞-细胞黏附分子，钙粘附素，在 Schlemm管内皮细胞。钙粘附素形成黏附连接复合体，存在于 传统的排水途径，但仅从形态上进行了描述。因为嗜同型蛋白- 相邻细胞上钙粘蛋白胞外区的蛋白质相互作用对形成和 维持至少三个细胞间连接复合体的完整性(包括粘附剂， 闭塞和缝隙)，已发表的证据表明细胞-细胞黏附在决定 流出阻力，我们假设Schlemm管内皮细胞之间的钙粘附素强烈影响 流出阻力的产生。 我们的研究将在分子和功能水平上检测钙粘附素，并(I)特异性地针对钙粘附素-5 (加上相关的连接素蛋白)和破坏Schlemm管内皮细胞之间的粘连；(Ii)分析 压力差/拉伸对相对表达水平、亚细胞分布和 钙粘蛋白-5和相关连环蛋白的磷酸化状态；以及(Iii)监测信号蛋白， 调节钙粘蛋白-5连接复合体的形成和重塑。从这些数据中获得的结果 研究将提供对钙粘附素蛋白在房水流出中的作用的基本了解。 抵抗和发现青光眼治疗的新治疗靶点。

Recent clinical trials demonstrate that significant, sustained intraocular pressure reduction in people with glaucoma slows or halts vision loss, even in patients with low-tension glaucoma. While the site of increased resistance in glaucoma is likely located in the conventional drainage pathway, the cellular mechanisms responsible for generation of this extra resistance are unknown. Previous work points to two possibilities that are not mutually exclusive: (i) abnormal accumulation and/or alterations in the extracellular matrix materials of the juxtacanalicular tissue; or (ii) alterations in the function of the intercellular junctions (and associated border pores) of the inner wall of Schlemm's canal. In the present application, we propose to study a family of cell-cell adhesion molecules, the cadherins, in the endothelial cells of Schlemm's canal. Cadherins form adherens junctional complexes, which are present in the conventional drainage pathway, but have only been described morphologically. Since homophilic protein- protein interactions of cadherin extracellular domains on adjacent cells are critical to the formation and maintenance of the integrity of at least three intercellular junctional complexes (including adherens, occludens and gap), and published evidence suggests that cell-cell adhesion plays a role in determining outflow resistance, we hypothesize that cadherins between Schlemm's canal endothelia strongly influence the generation of outflow resistance. Our study will examine cadherins at the molecular and functional levels and (i) specifically target cadherin-5 (plus associated catenin proteins) and disrupt adhesion between Schlemm's canal endothelia; (ii)analyze effects of pressure differences/stretch on relative expression levels, subcellular distribution and phosphorylation status of cadherin-5 plus associated catenins; and (iii) monitor signaling proteins that regulate the formation and remodeling of the cadherin-5 junction complex. Results obtained from these investigations will provide a basic understanding of the role of cadherin proteins in aqueous outflow resistance and uncover novel therapeutic targets for glaucoma therapy.