CADHERIN DYNAMICS AND GLAUCOMA

最近的临床试验表明，显著，持续的眼内压降低， 青光眼减缓或阻止视力丧失，即使是低眼压性青光眼患者。虽然网站的增加 青光眼中的阻力可能位于传统的引流途径，细胞机制 负责产生这种额外的阻力是未知的。以前的工作指出了两种可能性， （i）细胞外基质物质的异常积累和/或改变 （ii）细胞间连接功能的改变（以及相关的 Schlemm管内壁的边缘孔）。 在本申请中，我们提出研究细胞-细胞粘附分子家族，钙粘蛋白，其在细胞中的表达。 Schlemm管内皮细胞。钙粘蛋白形成粘附连接复合物，其存在于 传统的引流途径，但仅在形态学上进行了描述。因为嗜同性蛋白质- 钙粘蛋白胞外结构域与相邻细胞的蛋白质相互作用对于钙粘蛋白的形成和 维持至少三种细胞间连接复合物（包括粘附物， occludens和gap），已发表的证据表明，细胞-细胞粘附在决定 流出阻力，我们假设Schlemm管内皮细胞之间的钙粘蛋白强烈影响 流出阻力的产生。 我们的研究将在分子和功能水平上研究钙粘蛋白，（i）特异性靶向钙粘蛋白-5 (plus相关的连环蛋白），并破坏施累姆氏管内皮细胞之间的粘附;（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加上相关连环蛋白的磷酸化状态;和（iii）监测 调节钙粘蛋白-5连接复合物的形成和重塑。从这些获得的结果 调查将提供一个基本的了解钙粘蛋白蛋白的作用，在水流出 并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.