The Role of Complement System in Glaucoma

描述（由申请人提供）：青光眼是全球范围内致盲的主要原因，并继续构成临床挑战。这组疾病的特征在于视网膜神经节细胞（RGC）及其轴突的缓慢、进行性损失，并且在临床上通过视神经乳头的特征性变化和由此产生的视野损失来识别。虽然在该病的诊断和治疗方面有了许多改进，但其分子发病机制的许多方面仍不清楚，视力丧失仍不可逆转。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，并可能引起神经胶质细胞活化，对神经元细胞具有潜在的有害后果。在几种疾病模型中，补体的抑制已显示出神经保护作用。来自该实验室和其他实验室的数据已经证明，补体系统的组分在神经视网膜的青光眼变性早期局部合成，并且形成溶细胞C5 b-9复合物。补体成分特异性地与RGC相关地积累。使用视网膜损伤的缺血性模型，我们还提供了功能数据，证明补体对RGC损失有积极作用。最后，我们提出的初步数据表明，在补体成分基因突变有助于发展青光眼的风险在人类。该应用基于补体响应于RGC应激而合成并积极促进RGC快速死亡，从而限制活跃神经炎症的时间的假设。我们进一步假设，抑制补体级联调节青光眼中RGC和轴突损失的速率和程度。使用高眼压的啮齿动物模型、细胞培养物、人眼供体组织和青光眼患者的DNA，我们提出1）通过在补体缺陷小鼠中诱导高眼压以确定RGC损伤是否减轻来功能性地测试假设2）鉴定应激RGC上的C1 q配体和3）验证补体组分基因中的突变与青光眼的发展相关。本研究旨在描述补体系统在青光眼中的作用。这些研究还将确定该疾病的遗传风险因素，并确定补体反应的调节是否代表青光眼的潜在神经保护治疗。公众健康相关性：项目叙述青光眼是工业化国家视力丧失和失明的主要原因。更好地了解导致这种疾病中视网膜破坏的分子事件将有助于开发新的治疗方式。我们建议确定补体系统激活的功能意义，最近描述的和潜在的细胞毒性过程中，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.