The Role of Complement System in Glaucoma

描述(由申请人提供)：青光眼是世界范围内导致失明的主要原因，并继续构成临床挑战。这组疾病的特点是视网膜神经节细胞(RGC)及其轴突缓慢进行性丧失，临床上可通过视神经头的特征性变化和由此导致的视野丧失来识别。虽然该病的诊断和治疗有了许多改进，但其分子发病机制的许多方面仍然不清楚，视力丧失仍然是不可逆转的。最近的研究表明，补体的促炎性质可以加剧神经退行性疾病，并可能引发神经胶质细胞的激活，从而对神经细胞产生潜在的有害后果。在几种疾病模型中，抑制补体已被证明具有神经保护作用。来自该实验室和其他实验室的数据表明，补体系统的组成部分在青光眼视网膜神经变性的早期局部合成，并形成了溶解细胞的C5b-9复合体。补体成分与RGC相关而特别积累。使用视网膜损伤的缺血模型，我们还提供了功能数据，表明补体对RGC丢失有积极的贡献。最后，我们提供了初步数据，表明补体成分基因突变有助于人类发生青光眼的风险。这一应用是基于这样的假设，即补体是在RGC应激反应中合成的，并积极促进RGC迅速死亡，从而限制了活跃的神经炎症时期。我们进一步假设，抑制补体级联调节青光眼中RGC和轴突丢失的速度和程度。使用高眼压的啮齿动物模型、细胞培养、人眼供体组织和青光眼患者的DNA，我们建议1)通过在补体缺乏小鼠诱导高眼压来验证这一假设，以确定RGC损伤是否得到缓解；2)确定应激RGC上的C1q配体；3)验证补体成分基因的突变与青光眼的发展相关。本研究旨在探讨补体系统在青光眼中的作用。这些研究还将确定这种疾病的遗传风险因素，并确定补体反应的调节是否代表着一种潜在的青光眼神经保护治疗方法。公共卫生相关性：项目叙述青光眼是工业化世界中导致视力丧失和失明的主要原因。更好地了解这种疾病中导致视网膜破坏的分子事件将有助于开发新的治疗模式。我们建议确定补体系统激活的功能意义，这是最近描述的一种潜在的细胞毒性过程，发生在青光眼视网膜。

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.