CADHERIN REGULATION OF AQUEOUS HUMOR OUTFLOW

青光眼是美国第二大不可逆性失明原因，是一组以视网膜神经节细胞进行性丧失为特征的疾病，伴随着视力的丧失，在大多数情况下与眼压升高1-3相一致。今天和在可预见的未来，青光眼患者可以通过控制IP的药物进行临床治疗。青光眼患者的高眼压似乎是由于眼压调节过程存在缺陷所致，这意味着维持正常眼压会增加眼压流出阻力/4-7。目前青光眼研究的一个重点领域是了解房水流出阻力调节的分子和细胞机制。在目前的建议中，我们以一种新颖的方式研究了房水在流出通道中的调节。我们将研究一族跨膜细胞-细胞黏附分子，钙粘附素，在人类流出途径的细胞中。钙粘附素形成黏附功能复合体，在流出途径中仅在形态水平上被描述。由于同嗜性蛋白：钙粘附素的胞外域与相邻流出细胞的蛋白质相互作用对于细胞间连接复合体(包括粘附物、闭塞物和缝隙)的完整性至关重要，我们假设钙粘附素在流出阻力的产生中起着重要作用。我们的研究将在分子水平上检测这些蛋白质，并a)确定TM和SC细胞中存在的亚型(正常和青光眼)，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)监测调节粘附性复合体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对钙粘蛋白亚型在房水流出阻力中作用的基本了解，发现青光眼治疗的新治疗靶点，并为未来的研究奠定基础。

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.