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：青光眼集体指的是一组分子依据的眼部疾病。 全球初级敞开角度青光眼（POAG）是失明的主要原因之一，目前是无法治愈的。 POAG的区分症状是眼内压（IOP）和青光眼神经病变增加。通过过滤小梁网（TM）组织对水流的抗性增加似乎在POAG的发作和进展中起关键作用。小梁网级的阻塞导致IOP增加。对正常和青光眼TM的蛋白质组学和西方分析表明，Cochlin是一种分泌功能的分泌蛋白，仅在青光眼中呈现，但在正常TM中不存在。随后，我们还观察到通过青光眼TM中的免疫组织化学含有沉积物的Cochlin。在人耳蜗中，科克林与逐渐听觉功能障碍中的粘多糖沉积物有关。在TM中，Cochlin和粘多糖的沉积可能会干扰水性流出的调节，并可能导致IOP的缓慢而渐进的升高。我们已经将这些研究扩展到小鼠，发现Cochlin水平在青光眼的DBA/2J模型中升高，但在对照动物中没有升高。这里提出的研究将使用小鼠模型来确定Cochlin在IOP中的作用 海拔。要测试的中心假设是细胞外基质阻塞中的科克林沉积物 青光眼TM中的水流，提升IOP并有助于POAG的发病机理。该项目的长期目标是建立科奇林在IOP升高和POAG发病机理中的机械参与，并开发有效的疗法来预防疾病进展。我们的假设将通过以下特定目的进行检验：（1）确定Cochlin过表达是否导致IOP升高； （2）确定缺乏Cochlin的DBA/2J小鼠是否保持正常IOP； （3）测试Cochlin消息下调是否导致DBA/2J鼠标中的正常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。