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.

青光眼是一组分子基础尚不清楚的眼部疾病的统称。 原发性开角型青光眼（POAG）是世界范围内致盲的主要原因之一，目前无法治愈。POAG的显著症状是眼内压升高和青光眼性视神经病变。通过滤过性小梁网（TM）组织的房水流出阻力增加似乎在POAG的发病和进展中起关键作用。小梁网水平的阻塞导致IOP升高。蛋白质组学和蛋白质组学分析正常和脑胶质瘤TM揭示cochlin，分泌蛋白与未知功能，目前只在脑胶质瘤，但不是在正常TM。随后，我们还观察到cochlin含有存款免疫组化在青光眼TM。在人类耳蜗中，cochlin与进行性听觉功能障碍中的粘多糖沉积有关。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IOP缓慢但进行性升高。我们已经将这些研究扩展到小鼠，并发现cochlin水平在青光眼的DBA/2 J模型中升高，但在对照动物中没有升高。本文提出的研究将使用小鼠模型来确定cochlin在IOP中的作用。 提升待检验的中心假设是细胞外基质中的cochlin沉积物阻碍了细胞的生长。 青光眼TM的房水外流，升高IOP，并有助于POAG的发病机制。该项目的长期目标是建立cochlin参与IOP升高和POAG发病机制的机制，并开发有效的治疗方法来预防疾病进展。我们的假设将通过以下具体目的进行检验：（1）确定cochlin过表达是否导致IOP升高;（2）确定缺乏cochlin的DBA/2 J小鼠是否维持正常IOP;（3）测试cochlin信息下调是否导致DBA/2 J小鼠的正常IOP。方法将包括眼内注射、IOP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。