CADHERIN REGULATION OF AQUEOUS HUMOR OUTFLOW

青光眼是美国不可逆性失明的第二大主要原因，是一组特征为视网膜神经节细胞进行性丧失的疾病，伴有视力丧失，在大多数情况下与眼内压（IOP）升高一致1-3。 今天和在可预见的未来，青光眼患者的临床管理与控制IP的药剂。青光眼患者的IOP升高似乎是维持正常IOP的调节过程缺陷的函数，导致外流阻力增加/4-7。目前青光眼研究的重点领域是了解调节房水流出阻力的分子和细胞机制。在目前的建议中，我们研究了一种新的方式在外流途径的调节房水。我们将研究一个跨膜细胞间粘附分子家族，钙粘蛋白，在人类外流途径的细胞中。钙粘蛋白形成粘附素功能复合物，其在流出途径中仅在形态学水平上被描述。由于相邻流出细胞上的钙粘蛋白胞外结构域的嗜同性蛋白：蛋白相互作用在细胞间连接复合物（包括粘附蛋白、闭合蛋白和间隙）的完整性中是关键的，我们假设钙粘蛋白显著地有助于流出阻力的产生。我们的研究将在分子水平上检查这些蛋白，并且a）鉴定TM和SC细胞（正常和昏迷）中存在的亚型，B）分析压力/流量对相对表达水平、亚细胞分布和周转的影响，以及c）监测调节粘附蛋白复合物中蛋白质的形成和重塑的信号分子。如果成功，从这些研究中获得的结果将提供一个基本的了解的作用，钙粘蛋白亚型的水外流阻力，发现新的治疗目标青光眼治疗，并为未来的调查产生的基础。

Glaucoma, the second leading cause of irreversible blindness in the United States, is a group of disorders characterized by progressive loss of retinal ganglion cells with associated loss of vision that is in most cases coincident with elevated intraocular pressure (IOP)1-3. Today and in the foreseeable future, those with glaucoma are managed clinically with pharmaceutical agents that control IP. Elevated IOP in those with glaucoma appears to be a function of defective regulatory processes mean to maintain normal IOP that result in increased resistance to outflow/4-7. A current area of focus for glaucoma research is to understand the molecular and cellular mechanisms that underlie the regulation of aqueous outflow resistance. In the present proposal, we examine the regulation of aqueous humor in the outflow pathway in a novel manner. We will study a family of transmembrane cell-cell adhesion molecules, the cadherins, in the cells of the human outflow pathway. Cadherins form adheren function complex that in the outflow pathway have only been described at the morphological level. Since homophilic protein:protein interactions of the extracellular domains of cadherins on adjacent outflow cells are critical in the integrity of intercellular junctional complexes (including adherens, occludens and gap), we hypothesize that cadherens contribute significantly to the generation of outflow resistance Our study will examine these proteins at the molecular level and a) identify the subtypes present in both TM and SC cells (normal and glaucomatous), b) analyze effects of pressure/flow on relative expression levels, subcellular distribution and turnover and c) monitor signaling molecules that regulate the formation and remodeling of proteins in the adheren complex. If successful, results obtained from these investigations will provide a basic understanding of the role of cadherin subtypes in aqueous outflow resistance, uncover novel therapeutic targets for glaucoma therapy and generate a foundation for future investigations.