TRABECULAR MESHWORK PROTEINS IN GLAUCOMA

青光眼中的小梁网蛋白

• 批准号: 7659537
• 负责人: Sanjoy K Bhattacharya
• 金额: $ 29.71万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659537
• 关键词: Age; Alleles; Auditory; Biological; Blindness; Breeding; Cells; Cochlea; Control Animal; Deposition; Disease Progression; Down-Regulation; Extracellular Matrix; Eye; Eye diseases; Functional disorder; Genes; Glaucoma; Glycosaminoglycans; Goals; Human; Immunohistochemistry; Injection of therapeutic agent; Knock-out; Lentivirus Vector; Measurement; Messenger RNA; Methods; Modeling; Molecular; Mus; Optic Nerve; Pathogenesis; Physiologic Intraocular Pressure; Play; Primary Open Angle Glaucoma; Process; Proteins; Proteomics; Regulation; Resistance; Role; Site; Small Interfering RNA; Symptoms; Techniques; Testing; Time; Tissues; Trabecular meshwork structure; Viral; Virus Diseases; aqueous; base; congenic; effective therapy; mouse model; novel; optic nerve disorder; prevent; small hairpin RNA

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.

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）是导致失明的主要原因之一，目前无法治愈。 POAG 的显着症状是眼压 (IOP) 升高和青光眼性视神经病变。房水通过过滤性小梁网 (TM) 组织流出的阻力增加似乎在 POAG 的发生和进展中发挥着关键作用。小梁网水平的阻塞会导致眼压升高。对正常和青光眼 TM 的蛋白质组学和西方分析表明，cochlin（一种功能未知的分泌蛋白）仅存在于青光眼患者中，但不存在于正常 TM 中。随后我们还通过免疫组织化学在青光眼TM中观察到含有cochlin的沉积物。在人类耳蜗中，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，耳蜗蛋白和粘多糖的沉积可能会干扰房水流出的调节，并可能导致 IOP 缓慢但进行性升高。我们将这些研究扩展到小鼠，发现在 DBA/2J 青光眼模型中，cochlin 水平升高，但在对照动物中则没有升高。这里提出的研究将使用小鼠模型来确定耳蜗蛋白在眼压中的作用 海拔。要测试的中心假设是，细胞外基质中的耳蜗蛋白沉积物阻碍 青光眼 TM 中房水流出，导致 IOP 升高，并导致 POAG 的发病机制。该项目的长期目标是确定耳蜗蛋白在 IOP 升高和 POAG 发病机制中的参与机制，并开发预防疾病进展的有效疗法。我们的假设将通过以下具体目标进行检验：（1）确定cochlin过度表达是否会导致眼压升高； (2)测定缺乏cochlin的DBA/2J小鼠是否维持正常眼压； (3)检测Cochlin信息下调是否导致DBA/2J小鼠眼压正常。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。