TRABECULAR MESHWORK PROTEINS IN GLAUCOMA

描述：青光眼是一组眼部疾病的统称，其分子基础尚不清楚。在世界范围内，原发性开角型青光眼（POAG）是致盲的主要原因之一，目前无法治愈。POAG的主要症状是眼压升高和青光眼性视神经病变。通过滤过小梁网（TM）组织的水流出阻力增加似乎在POAG的发生和发展中起关键作用。小梁网水平的阻塞导致IOP升高。正常和青光眼TM的蛋白质组学和Western分析显示，耳蜗蛋白是一种功能未知的分泌蛋白，只存在于青光眼TM中，而不存在于正常TM中。随后，我们也通过免疫组化观察到青光眼TM中含有耳蜗的沉积物。在人耳蜗中，耳蜗蛋白与进行性听觉功能障碍中的粘多糖沉积有关。在TM中，耳蜗和粘多糖的沉积可能会干扰水流出的调节，并可能导致缓慢但渐进的IOP升高。我们将这些研究扩展到小鼠，发现DBA/2J青光眼模型中耳蜗素水平升高，而对照组动物中没有。本文提出的研究将使用小鼠模型来确定耳蜗在IOP中的作用

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.