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，青光眼患者显着、持续的眼内压降低可以减缓或停止视力丧失，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，但导致这种额外阻力产生的细胞机制尚不清楚。先前的工作指出了两种并不相互排斥的可能性：（i）近小管组织的细胞外基质材料的异常积累和/或改变； (ii) 施累姆氏管内壁细胞间连接（以及相关的边界孔）功能的改变。在本申请中，我们建议研究施累姆氏管内皮细胞中的细胞间粘附分子家族，即钙粘蛋白。钙粘蛋白形成粘附连接复合物，其存在于常规引流途径中，但仅在形态学上进行了描述。由于相邻细胞上钙粘蛋白胞外结构域的同亲蛋白-蛋白相互作用对于至少三个细胞间连接复合物（包括粘附、闭塞和间隙）的完整性的形成和维持至关重要，并且已发表的证据表明细胞-细胞粘附在确定流出阻力中发挥作用，因此我们假设施累姆氏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检查钙粘蛋白，并且（i）特异性靶向钙粘蛋白-5（加上相关联蛋白）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 cadherin-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； (iii) 监测调节钙粘蛋白-5 连接复合物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房水流出阻力中的作用的基本了解，并揭示青光眼治疗的新治疗靶点。