CD274调控小胶质细胞参与视网膜色素上皮细胞损伤保护及其分子机制研究

年龄相关性黄斑变性（AMD）是老年人致盲的首要因素之一，而RPE退行性变性是干性AMD致病的主要因素。小胶质细胞过度活化会加速视网膜退变，最新研究表明利用关键调节分子如TGF-β1能重塑小胶质细胞，抑制视网膜变性并保护视功能。但在干性AMD发展中小胶质细胞的功能和关键调节分子尚不清楚。在前期小鼠干性AMD模型的研究中，我发现CD274-PD1信号通路能调控小胶质细胞的免疫活性从而发挥对RPE的保护作用。本项目拟利用腺相关病毒介导的过表达体系进一步验证CD274在干性AMD模型中的保护功能，并利用STAT3抑制剂和活化因子，解析CD274通过STAT3调控小胶质细胞免疫活性的分子机制，并结合干性AMD模型进行在体验证。这一原创性研究旨在阐明小胶质细胞在干性AMD发展中的免疫调节机制，加深对RPE损伤修复机制的认识，为利用靶向CD274-PD1的干性AMD转化医学研究提供前瞻性思路和实验依据。

Age-related macular degeneration (AMD), including dry AMD and wet AMD, is one of the major causative factors of blindness. RPE degeneration plays key roles during dry AMD pathologies. Hyperactivation of microglia leads to accelerated retinal degeneration. Surprisingly, recent studies indicated that microglia modulated by key regulators, such as TGF-β1, could inhibit retinal degeneration and protect vision. However, functional roles of microglia during progress of dry AMD, along with its key regulators, are not fully clear. Our previous results show that CD274-PD1 signaling was able to regulate immunological activities of microglia, which in turn protect RPE from injuries. In this proposal, we are planning to utilize adeno-associated virus mediated gene over-expression to confirm protective roles of CD274 in dry AMD，and to utilize both inhibitor and activator of STAT3 to dissect molecular mechanisms of immunological activities of microglia regulated by CD274-PD1 signaling. These results will be further confirmed in the dry AMD animal model. We think that the outcomes from this original proposal will illustrate underlying molecular mechanisms of immune regulations of microglia in dry AMD pathologies, and provide theoretical and experimental bases for therapeutic approaches targeting CD274-PD1 signaling in dry AMD.