视网膜色素上皮细胞对维持视网膜下腔免疫豁免中补体活化的调控

The retina is an immune privileged tissue. The retinal pigment epithelial cell plays a critical role in maintaining this immune privilege. Loss of immune privilege is related to many sight-threatening eye diseases such as Age-related Macular Degeneration (AMD). We believe RPE cells maintain immune privilege in subretinal space not only by suppressing immune cell activation and inducing apoptotic cell death, but also by inhibiting complement activation. The excessive activation of the complement system has been widely implicated in the occurrence and development of AMD and uveoretinitis. In this proposal, we aim to further our understanding on the complement activation mechanisms in eye diseases such as AMD by investigating the role of RPE cells in regulating complement activation in subretinal space. First, we will systemically investigate how RPE cells regulate complement activation under normal physiological condition, including modulation of complement inhibitory and activation factors expression and secretion by RPE itself, and its impact on complement factors generated from other cells, such as subretinal microglia/macrophages. Then, we will investigate further into how this regulating is dysregulated under oxidative stress and inflammatory conditions. Importantly, we will investigate the role of RPE-origin complement inhibitory factors (C1INH and C4BP) on the subretinal space immune privilege.

视网膜是具有免疫豁免的组织。视网膜色素上皮（RPE）是维持视网膜下腔免疫豁免的关键细胞。该区域免疫豁免的丧失与常见眼病如AMD密切相关。我们认为RPE不仅通过抑制免疫细胞活化和诱导凋亡，还通过抑制补体活化以维持视网膜下腔免疫豁免。补体的过度活化与AMD 和葡萄膜炎等的发生与发展有密切关系。本项目拟通过对RPE在视网膜下腔补体活化中调控的研究，深入了解在AMD等眼病中补体过度活化的机制。首先，我们将系统研究在正常生理状态下RPE是如何调节补体活化的，包括对自身表达和分泌补体抑制因子及活化因子的调控和对其他细胞，如视网膜下腔小胶质细胞/巨噬细胞补体因子分泌及活化的调控。然后，我们将进一步研究在受到氧化应激及炎症条件下RPE对补体活化的调节是如何失控的。最后，我们将通过改变RPE补体调控蛋白（C1INH、C4BP）的表达，进一步探讨补体调节系统对视网膜下腔免疫豁免的影响。

本研究通过对 视网膜色素上皮细胞在正常生理及损伤条件下对视网膜下腔补体活化调控的研究，进一步确认了巨噬细胞与视网膜色素上皮细胞在相互作后的表型变化与功能调控，如C1INH的表达变化，细胞分群的变化，对补体介导的炎症调控的影响，T细胞吞噬能力的变化等。小胶质细胞/巨噬细胞在视网膜下腔的这一功能退化如何促进进感光细胞/RPE细胞的退行性病变的机理也非常值得深入研究。C1INH作为plasma kallikrein介导的视网膜血管渗漏、水肿等病理变化中的重要抑制因子，我们通过C1INH过表达与敲降的细胞与病毒工具，通过动物模型进一步研究针对糖尿病视网膜病变、黄斑变性等新药研发过程中以plasma kallikrein为靶点的药物设计上C1INH作为联用因子的可行性。