The Role of Complement System in Glaucoma

补体系统在青光眼中的作用

• 批准号: 8317676
• 负责人: MARKUS H. KUEHN
• 金额: $ 35.64万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8317676
• 关键词: Animal Model; Axon; Binding; Biological Markers; Biological Models; Biological Preservation; Blindness; Cell Culture System; Cell Culture Techniques; Cell Death; Cell surface; Cells; Cellular Stress; Cessation of life; Characteristics; Clinical; Clinical Management; Collection; Complement; Complement 1q; Complement Activation; Complement Component Gene; Complement Membrane Attack Complex; Complex; DNA; Data; Deposition; Development; Diagnosis; Disease; Disease model; Distress; Event; Excision; Eye; Familiarity; Functional disorder; Genes; Glaucoma; Goals; Health; Human; Iowa; Laboratories; Lead; Ligands; Macular degeneration; Mediating; Methods; Modality; Modeling; Molecular; Mus; Mutation; Nature; Neural Retina; Neurodegenerative Disorders; Neurons; Ocular Hypertension; Optic Disk; Pathogenesis; Pathway interactions; Patients; Physiologic Intraocular Pressure; Physiological; Primary Open Angle Glaucoma; Process; Regimen; Reporting; Research Personnel; Retina; Retinal; Retinal Diseases; Retinal Ganglion Cells; Risk; Rodent Model; Role; Sampling; Stress; Testing; Tissue Donors; Universities; Variant; Vision; Visual Fields; Work; base; cell injury; cellular targeting; complement system; cytotoxic; design; expectation; genetic risk factor; injured; innovation; neuroinflammation; neuronal cell body; novel; novel strategies; novel therapeutics; optic nerve disorder; response; retinal damage; Animal Model; Axon; Binding; Biological Markers; Biological Models; Biological Preservation; Blindness; Cell Culture System; Cell Culture Techniques; Cell Death; Cell surface; Cells; Cellular Stress; Cessation of life; Characteristics; Clinical; Clinical Management; Collection; Complement; Complement 1q; Complement Activation; Complement Component Gene; Complement Membrane Attack Complex; Complex; DNA; Data; Deposition; Development; Diagnosis; Disease; Disease model; Distress; Event; Excision; Eye; Familiarity; Functional disorder; Genes; Glaucoma; Goals; Health; Human; Iowa; Laboratories; Lead; Ligands; Macular degeneration; Mediating; Methods; Modality; Modeling; Molecular; Mus; Mutation; Nature; Neural Retina; Neurodegenerative Disorders; Neurons; Ocular Hypertension; Optic Disk; Pathogenesis; Pathway interactions; Patients; Physiologic Intraocular Pressure; Physiological; Primary Open Angle Glaucoma; Process; Regimen; Reporting; Research Personnel; Retina; Retinal; Retinal Diseases; Retinal Ganglion Cells; Risk; Rodent Model; Role; Sampling; Stress; Testing; Tissue Donors; Universities; Variant; Vision; Visual Fields; Work; base; cell injury; cellular targeting; complement system; cytotoxic; design; expectation; genetic risk factor; injured; innovation; neuroinflammation; neuronal cell body; novel; novel strategies; novel therapeutics; optic nerve disorder; response; retinal damage

DESCRIPTION (provided by applicant): Glaucoma is a leading cause of blindness worldwide and continues to pose a clinical challenge. This group of diseases is characterized by the slow, progressive loss of retinal ganglion cells (RGC) and their axons, and is clinically recognized by characteristic changes to the optic nerve head and resultant visual field loss. Although there have been many improvements in the diagnosis and treatment of the disease, many aspects of its molecular pathogenesis remain unclear and loss of vision remains irreversible. Recent work indicates that the proinflammatory nature of complement can exacerbate neurodegenerative disease and is likely to elicit glial activation with potentially harmful consequences to neuronal cells. In several disease models inhibition of complement has been shown to be neuroprotective. Data from this and other laboratories has demonstrated that components of the complement system are locally synthesized early during the glaucomatous degeneration of the neural retina and that the cytolytic C5b-9 complex is formed. Complement components specifically accumulate in association with RGC. Using an ischemic model of retinal damage we have also provided functional data demonstrating that complement actively contributes to RGC loss. Finally, we present preliminary data suggesting that mutations in complement component genes contribute to the risk of developing glaucoma in humans. This application is based upon the hypothesis that complement is synthesized in response to RGC stress and actively promotes rapid RGC death, thereby limiting the period of active neuroinflammation. We further hypothesize that inhibition of the complement cascade modulates the rate and extent of RGC and axonal loss in glaucoma. Using a rodent model of ocular hypertension, cell culture, human eye donor tissue, and DNA from glaucoma patients we propose to 1) functionally test the hypothesis by inducing ocular hypertension in complement deficient mice to determine if RGC damage is mitigated 2) identify the C1q ligand on stressed RGC and 3) verify that mutations in complement component genes are associated with the development of glaucoma. This study is aimed to characterize the role of the complement system in glaucoma. These studies will also identify a genetic risk factor for the disease and determine if modulation of the complement response represents a potential neuroprotective treatment for glaucoma. PUBLIC HEALTH RELEVANCE: Project Narrative Glaucoma is a leading cause of vision loss and blindness in the industrialized world. A better understanding of the molecular events to lead to the destruction of the retina in this disease will benefit the development of novel treatment modalities. We propose to determine the functional significance of complement system activation, a recently described and potential cytotoxic process, which occurs in the glaucomatous retina.

描述（由申请人提供）：青光眼是全球失明的主要原因，并继续构成临床挑战。这组疾病的特征是视网膜神经节细胞（RGC）及其轴突的缓慢，进行性逐渐丧失，并且在临床上以视神经头的特征变化和由此导致的视野损失而被临床识别。尽管该疾病的诊断和治疗有很多改善，但其分子发病机理的许多方面仍然不清楚，视力丧失仍然是不可逆转的。最近的工作表明，补体的促炎性质会加剧神经退行性疾病，并可能引起神经胶质激活，并可能对神经元细胞产生潜在有害的后果。在几种疾病模型中，抑制补体已显示为神经保护作用。来自该实验室和其他实验室的数据表明，在神经视网膜的青光眼变性期间，补体系统的组成部分是局部合成的，并且形成了细胞溶解的C5B-9复合物。与RGC相关的补体成分。使用视网膜损伤的缺血模型，我们还提供了功能数据，证明补体积极促进RGC损失。最后，我们提供了初步数据，表明补体成分基因中的突变有助于人类发展青光眼的风险。该应用是基于以下假设：补体是响应RGC应力而合成的，并积极促进RGC死亡，从而限制了主动神经炎症的时期。我们进一步假设抑制补体级联反应调节青光眼中RGC和轴突损失的速率和程度。 Using a rodent model of ocular hypertension, cell culture, human eye donor tissue, and DNA from glaucoma patients we propose to 1) functionally test the hypothesis by inducing ocular hypertension in complement deficient mice to determine if RGC damage is mitigated 2) identify the C1q ligand on stressed RGC and 3) verify that mutations in complement component genes are associated with the development of glaucoma.这项研究旨在表征补体系统在青光眼中的作用。这些研究还将确定疾病的遗传危险因素，并确定补体反应的调节是否代表了青光眼的潜在神经保护治疗。公共卫生相关性：项目叙事青光眼是工业化世界中视力丧失和失明的主要原因。更好地理解分子事件，导致在这种疾病中破坏视网膜的事件将有益于新型治疗方式的发展。我们建议确定补体系统激活的功能意义，这是一种最近描述的和潜在的细胞毒性过程，发生在青光眼视网膜中。