CADHERIN DYNAMICS AND GLAUCOMA

钙粘蛋白动力学和青光眼

• 批准号: 7350116
• 负责人: W Daniel Stamer
• 金额: $ 33.22万
• 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/7350116
• 关键词: Adherens Junction; Adhesions; Anterior; Aqueous Humor; Area; Binding; Biological Models; Biology; Biomechanics; Blindness; Blood Vessels; Cadherins; Calcium; Cell Adhesion Molecules; Cell-Cell Adhesion; Cells; Clinical Trials; Complex; Data; Developed Countries; Developing Countries; Development; Drainage procedure; Endothelial Cells; Endothelium; Extracellular Domain; Extracellular Matrix; Family; Generations; Genes; Glaucoma; Goals; Human; Individual; Intercellular Junctions; Investigation; Knowledge; Laboratories; Maintenance; Mechanics; Mediating; Molecular; Molecular and Cellular Biology; Monitor; Ocular Hypertension; Open-Angle Glaucoma; Outcome; Pathway interactions; Patients; Perfusion; Permeability; Pharmacologic Substance; Phosphorylation; Physiologic Intraocular Pressure; Play; Primary Open Angle Glaucoma; Proteins; Publishing; Qualifying; Range; Receptor Activation; Receptor Signaling; Recording of previous events; Regulation; Relative (related person); Research; Research Personnel; Resistance; Role; Signaling Protein; Site; Sphingosine-1-Phosphate Receptor; Stretching; Structure; Structure of sinus venosus of sclera; Technical Expertise; Testing; Thinking; Time; Tissues; Vision; Work; aqueous; base; cadherin 5; design; experience; extracellular; innovation; member; novel; novel therapeutics; pressure; programs; protein expression; protein protein interaction; therapeutic target; tool

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.

最近的临床试验表明，患有以下疾病的人的眼内压显着持续降低 青光眼可以减缓或阻止视力丧失，即使是低眼压青光眼患者也是如此。虽然网站增加了 青光眼的抵抗可能位于传统的引流途径，细胞机制 产生这种额外阻力的原因尚不清楚。之前的工作指出了两种可能性 并不相互排斥：（i）细胞外基质材料的异常积累和/或改变 近小管组织；或（ii）细胞间连接功能的改变（以及相关的 施莱姆管内壁的边界孔）。 在本申请中，我们建议研究细胞间粘附分子家族，钙粘蛋白， 施累姆氏管的内皮细胞。钙粘蛋白形成粘附连接复合物，存在于 传统的排水路径，但仅在形态上进行了描述。由于同亲蛋白- 相邻细胞上钙粘蛋白胞外结构域的蛋白质相互作用对于形成和 维持至少三个细胞间连接复合物的完整性（包括粘附、 occlusionns 和间隙），并且已发表的证据表明细胞-细胞粘附在决定 流出阻力，我们假设施累姆氏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检查钙粘蛋白，并且 (i) 专门针对钙粘蛋白-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； (二)分析 压力差/拉伸对相对表达水平、亚细胞分布和 cadherin-5 及相关连环蛋白的磷酸化状态； (iii) 监测信号蛋白 调节 cadherin-5 连接复合物的形成和重塑。从这些得到的结果 研究将提供对钙粘蛋白在房水流出中的作用的基本了解 耐药性并发现青光眼治疗的新治疗靶点。