CADHERIN DYNAMICS AND GLAUCOMA

钙粘蛋白动力学和青光眼

基本信息

批准号：
7583931
负责人：
W Daniel Stamer
金额：
$ 33.9万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
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/7583931
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 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 Time Tissues Vision Work aqueous base cadherin 5 design effective therapy experience extracellular innovation member new therapeutic target novel pressure programs protein expression protein protein interaction tool

项目摘要

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，患有大量的，持续的眼内压力降低青光眼减慢或停止视力丧失，即使在低压青光眼患者中也是如此。而增加的地点青光眼的耐药性可能位于常规排水途径中，该途径是细胞机制负责产生这种额外的抵抗力是未知的。以前的工作指出了两种可能性不是相互排斥的：（i）细胞外基质材料中异常的积累和/或改变近去核组织；或（ii）细胞间连接功能的变化（及相关 Schlemm运河内壁的边界孔。在本应用中，我们建议研究细胞细胞粘附分子家族，钙粘蛋白，在 Schlemm运河的内皮细胞。钙粘蛋白形成粘附连接络合物，存在于常规的排水途径，但仅在形态上描述。由于均匀蛋白质钙粘着蛋白外细胞在相邻细胞上的蛋白质相互作用对形成至关重要维持至少三个细胞间连接络合物的完整性（包括粘附，封闭式和差距），并发表的证据表明细胞 - 细胞粘附在确定中起作用我们假设Schlemm的运河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）专门针对钙粘蛋白-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/拉伸对相对表达水平，亚细胞分布和 Cadherin-5加上相关的蛋白酶的磷酸化状态；（iii）监测信号蛋白的信号蛋白调节钙粘蛋白-5连接络合物的形成和重塑。从这些结果获得的结果调查将提供对钙粘蛋白蛋白在水溶液中的作用的基本理解耐药性并发现了青光眼治疗的新型治疗靶标。