TRABECULAR MESHWORK PROTEINS IN GLAUCOMA

描述：青光眼是一组分子基础知之甚少的眼部疾病。全世界的原发性开角型青光眼(POAG)是导致失明的主要原因之一，目前是无法治愈的。POAG的主要症状是眼压升高和青光眼视神经病变。滤过性小梁网络(TM)组织对房水流出的抵抗力增加似乎在POAG的发生和发展中起关键作用。小梁网水平的阻塞会导致眼压升高。蛋白质组学和蛋白质组分析显示，Cochlin是一种功能未知的分泌性蛋白，仅存在于青光眼中，而在正常TM中不存在。随后，我们还通过免疫组织化学观察到青光眼TM中含有Cochlin的沉积。在人类耳蜗组织中，耳蜗素与进行性听觉功能障碍中粘多糖的沉积有关。在TM中，Cochlin和粘多糖的沉积可能干扰房水流出的调节，并可能导致缓慢但渐进性的眼压升高。我们将这些研究扩展到小鼠身上，发现在DBA/2J青光眼模型中，Cochlin水平升高，但在对照动物中没有。这里提出的研究将使用小鼠模型来确定Cochlin在IOP中的作用 立面。需要检验的中心假设是，细胞外基质中的可可林沉积阻碍了细胞外基质 青光眼TM房水流出，眼压升高，参与了POAG的发病。该项目的长期目标是建立Cochlin在眼压升高和POAG发病机制中的作用机制，并开发有效的治疗方法来防止疾病的进展。我们的假设将以下列特定目标进行验证：(1)确定cochlin过度表达是否会导致高眼压；(2)确定缺乏cochlin的DBA/2J小鼠是否保持正常的眼压；(3)测试cochlin信息下调是否导致DBA/2J小鼠正常的眼压。方法包括眼内注射、眼压测量、病毒感染、免疫组织化学以及其他分子和细胞生物学技术。

DESCRIPTION: Glaucoma refers collectively to a group of eye diseases whose molecular basis is poorly understood. Worldwide primary open angle glaucoma (POAG) is one of the leading causes of blindness and is currently incurable. Distinguishing symptoms of POAG are increased intraocular pressure (IOP) and glaucomatous optic neuropathy. Increased resistance to aqueous outflow through the filtering trabecular meshwork (TM) tissue appears to play a key role in the onset and progression of POAG. Blockage at the level of trabecular meshwork leads to increased IOP. Proteomic and Western analyses of normal and glaucomatous TM have revealed cochlin, a secreted protein with unknown function, present exclusively in glaucomatous but not in normal TM. Subsequently we have also observed cochlin containing deposits by immunohistochemistry in glaucomatous TM. In the human cochlea, cochlin is associated with mucopolysaccharide deposits in progressive auditory dysfunction. In the TM, deposition of cochlin and mucopolysaccharides may interfere with regulation of aqueous outflow and may cause slow but progressive elevation of IOP. We have extended these studies to mice and found that cochlin levels were elevated in the DBA/2J model of glaucoma but not in control animals. The studies proposed here will use mouse models to determine the role of cochlin in IOP elevation. The central hypothesis to be tested is that cochlin deposits in the extracellular matrix obstruct aqueous outflow in glaucomatous TM, elevate IOP and contribute to the pathogenesis of POAG. The long-term goals of this project are to establish the mechanistic involvement of cochlin in IOP elevation and the pathogenesis of POAG, and to develop effective therapies for preventing disease progression. Our hypothesis will be tested with following specific aims: (1) To determine whether cochlin over-expression results in elevated IOP; (2) To determine whether DBA/2J mice lacking cochlin maintain normal IOP; (3) To test whether cochlin message down-regulation results in normal IOP in DBA/2J mouse. Methods will include intraocular injections, IOP measurements, viral infections, immunohistochemistry as well as other molecular and cell biological techniques.