The Alternative Complement System Facilitates Photoreceptor Degeneration in Retinal Detachment.

项目摘要 视网膜脱离(RD)和随后的视网膜神经变性仍然是 视力受损。在持续RD的患者中，由于光感受器细胞死亡而导致的进行性视力下降 这很常见，并会导致视力显著下降。许多病理变化都发生在 分离的视网膜和对人类患者样本和动物模型的研究表明，快速光感受器 RD引起的细胞死亡。然而，促成这种死亡的潜在过程仍然存在。 难以捉摸，目前除了手术重新连接视网膜外，还没有其他治疗方法。早期炎症 在RD患者眼中，介体上调；尤其值得关注的是补体的介体 系统。补体系统是一种复杂的免疫监视系统，能够区分 在健康和患病的宿主组织之间，并相应地调节宿主组织的消除和修复。 在眼部微环境中，替代补体级联表现出低水平的构成成分 激活，并受到眼内补体调节蛋白的严格控制。我们最近发现， 替代补体途径是光感受器细胞在损伤反应中死亡的重要调节因子。 然而，关于这一途径如何在RD中被激活，人们知之甚少。有趣的是，补语 受体是强大的下游炎症介质，导致免疫细胞的募集和上调。 局部微环境对补体蛋白和促炎细胞因子的调节 我们的初步数据强烈表明补体受体与光感受器细胞死亡有关。为此，我们 假设补体受体及其各自的配体有助于促进对 受损视网膜中的应激光感受器，专门针对这些细胞进行移除，并增加 视网膜微环境中的炎症可能会加剧这种退行性疾病。我们将利用一个 明确的RD小鼠模型，在该模型中，视网膜下注射透明质酸钠来创建 超然。小鼠RD模型将允许我们利用已建立的基因操作 在受控环境中的小鼠身上的平台。为了刻画先天免疫系统在 光感受器细胞死亡我们将：1)确定补体受体在调节光感受器细胞中的作用 RD死亡(AIM I)；2)确定RD反应中补体产生的调节机制(AIM Ii)和3)确定补体受体和小胶质细胞在RD疾病发病机制中的作用(Aim III)。它 我们希望这项提案将使我们能够进一步确定补充制度在 RD期间光感受器丢失，导致将RD作为辅助治疗来保护个体的治疗 视网膜脱离手术的代理人。

Project Summary Retinal detachment (RD) and subsequent neurodegeneration of the retina continues to be a leading cause of visual impairment. In patients with sustained RD, progressive visual decline due to photoreceptor cell death is common and leads to a significant decrease in visual acuity. Numerous pathological changes occur in the detached retina and studies in human patient samples and in animal models have shown rapid photoreceptor cell death in response to RD. However, the underlying processes that facilitate this death have remained elusive and currently no treatments exist, aside from surgery to reattach the retina. Early inflammatory mediators are up-regulated in the eyes of patients with RD; of particular interest are those of the complement system. The complement system is an intricate immune surveillance system that is able to discriminate between healthy and diseased host tissue, and modulates the elimination and repair of host tissue accordingly. Within the ocular microenvironment, the alternative complement cascade exhibits low levels of constitutive activation and is tightly controlled by intraocular complement regulatory proteins. We have recently found that the alternative complement pathway is a vital regulator of photoreceptor cell death in response to injury. However, little is known about how this pathway becomes activated in RD. Interestingly, the complement receptors are potent downstream mediators of inflammation leading to the recruitment of immune cells and up- regulation of both complement proteins as well as pro-inflammatory cytokines from the local microenvironment Our preliminary data strongly implicates the complement receptors in photoreceptor cell death. To this end we hypothesize that the complement receptors, and their respective ligands, help facilitate a response against the stressed photoreceptors in the damaged retina, specifically targeting these cells for removal and increasing the inflammatory potential in the retinal microenvironment exacerbating this degenerative disease. We will utilize a well-defined mouse model of RD, in which a subretinal injection of sodium hyaluronate is used to create a detachment. The mouse RD model will allow us to take advantage of well-established genetic manipulation platforms in mice in a controlled setting. In order to characterize the role of the innate immune system in photoreceptor cell death we will: 1) Determine the role of complement receptors in mediating photoreceptor cell death in RD (Aim I); 2) Identify the regulatory mechanisms of complement production in response to RD (Aim II) and 3) To define the role of the complement receptors and microglia in RD disease pathogenesis (Aim III). It is our hope that this proposal will allow us to further characterize the role of the complement system in photoreceptor loss during RD, leading to therapies that protect individuals with RD as an adjuvant therapeutic agent to retinal detachment surgery.