CADHERIN DYNAMICS AND GLAUCOMA

钙粘蛋白动力学和青光眼

• 批准号: 7015408
• 负责人: W Daniel Stamer
• 金额: $ 36.19万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-02 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7015408
• 关键词: cadherins; glaucoma; human; proteins; role; sclera

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.

描述（由申请人提供）：最近的临床试验表明，即使在低张力青光眼患者中，青光眼降低或停止视力丧失的人的明显，持续的眼内压力降低。虽然青光眼中耐药性增加的部位可能位于常规排水途径中，但导致产生这种额外耐药性的细胞机制尚不清楚。先前的工作指出了两种非相互排斥的可能性：（i）近去核组织的细胞外基质材料的异常积累和/或改变；或（ii）Schlemm运河内壁的细胞间连接（以及相关边界孔）功能的变化。在本应用中，我们建议在Schlemm的运河的内皮细胞中研究一个细胞细胞粘附分子（钙粘蛋白）的家族。钙粘蛋白形成粘附的连接络合物，存在于常规排水途径中，但仅在形态上描述。由于钙粘蛋白在相邻细胞上的同粒细胞蛋白质蛋白质相互作用对于至少三种三个细胞间连接络合物的完整性形成和维持至关重要影响流出阻力的产生。我们的研究将检查分子和功能水平的钙粘蛋白，（i）特别靶向钙粘蛋白5（加上相关的蛋白酶蛋白），并破坏Schlemm的运河内皮之间的粘附； （ii）分析压力差异/拉伸对钙粘蛋白5和相关链球菌的相对表达水平，亚细胞分布和磷酸化状态的影响； （iii）监测调节钙粘蛋白-5连接复合物的形成和重塑的信号蛋白。从这些研究中获得的结果将提供对钙粘蛋白在水性流出抗性中的作用的基本理解，并发现青光眼治疗的新型治疗靶标。