CADHERIN DYNAMICS AND GLAUCOMA

描述（由申请人提供）：最近的临床试验表明，青光眼患者的显著持续眼内压降低可减缓或阻止视力丧失，即使是低眼压性青光眼患者也是如此。虽然青光眼中阻力增加的部位可能位于传统的引流途径中，但负责产生这种额外阻力的细胞机制尚不清楚。以前的工作指出了两种不相互排斥的可能性：（i）异常积累和/或改变的细胞外基质材料的小管组织;或（ii）改变的功能的细胞间连接（和相关的边界孔）的内壁Schlemm管。在本申请中，我们建议研究施累姆氏管内皮细胞中的细胞-细胞粘附分子家族，即钙粘蛋白。钙粘蛋白形成粘附连接复合物，其存在于传统的引流途径中，但仅在形态学上进行了描述。由于钙粘蛋白胞外结构域与相邻细胞之间的蛋白-蛋白相互作用对至少三种细胞间连接复合物的形成和维持至关重要，（包括粘附物、闭合物和间隙），并且已发表的证据表明细胞-细胞粘附在确定流出阻力中起作用，我们推测Schlemm管内皮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（ii）分析压力差/拉伸对钙粘蛋白-5加相关连环蛋白的相对表达水平、亚细胞分布和磷酸化状态的影响;和（iii）监测调节钙黏着蛋白-5连接复合物的形成和重塑的信号蛋白。从这些调查中获得的结果将提供一个基本的了解的作用，钙粘蛋白在水外流阻力，并发现新的治疗青光眼的治疗目标。

DESCRIPTION (provided by applicant): 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.