Fractalkine-CX3CR1介导的小胶质细胞失稳态在糖尿病视网膜微血管病变中的作用研究

Diabetic retinal microangiopathy has been a major focus of current research, with much effort being devoted to understanding the pathological changes and the theropy method. Recent results indicate that retinal microvascular endothelial cell(RMEC) damage induced by high glucose lead to microglial activation, which would be driven by the further destroy of inner blood retinal barrier(iBRB). Although the involvement of microglia is certain, the relationship between RMEC damage and microglial activation remains poorly understood. Mounting evidence suggest that the ligand–receptor pair fractalkine/CX3CR1 appear to be an ideal candidate to mediate RMEC/microglial interaction. In this work, we try to investigate the cross-talk between injured RMEC and activated retinal microglia, focusing on the role of fractalkine and its receptor CX3CR1 in diabetic retinal microangiopathy using both in vivo and in vitro models. We will evaluate the spatial and temporal relationship among iBRB damage, fractalkine/CX3CR1 impairment, and microglial homeostasis. Furthermore, we will explore the downstream intracellular signal transduction pathways. The purpose of this study is to find a novel therapeutic target in diabetic retinal microangiopathy.

糖尿病视网膜微血管病变的病理机制及治疗是目前研究的难点。近年来小胶质细胞的作用受到重视。高糖诱发视网膜微血管内皮细胞损伤后激活小胶质细胞，导致进一步内层血视网膜屏障损伤已得到证实。但内皮细胞损伤和小胶质细胞激活募集之间的分子对话机制仍不清楚，干预该过程或成为延缓糖尿病视网膜病变发展的关键。研究提示趋化因子Fractalkine及其受体CX3CR1可能是二者分子对话的重要介质。本研究拟采用STZ诱导糖尿病视网膜病变小鼠模型、体外小胶质细胞和微血管内皮细胞、周细胞共培养模式，研究Fractalkine/CX3CR1信号在高糖诱导微血管内皮细胞损伤后的时空变化，着力于分析该信号的变化规律及与小胶质细胞激活募集、内层血视网膜屏障破坏之间潜在的关系，并深入探讨其调控小胶质细胞激活募集的细胞内信号途径，阐明视网膜微血管损伤和小胶质细胞失稳态之间的分子机制，为延缓糖尿病视网膜病变的进展开拓治疗新思路。

糖尿病视网膜病变是一种视网膜微血管性疾病，其病理机制是目前研究的难点。小胶质细胞和内皮细胞/周细胞之间的对话被认为是视网膜微血管稳态的先决条件。研究提示趋化因子Fractalkine及其受体CX3CR1可能是二者分子对话的重要介质。.本研究采用STZ诱导糖尿病视网膜病变大鼠模型、体外小胶质细胞和微血管内皮细胞、周细胞共培养模式，研究发现高血糖损伤视网膜微血管内皮细胞可导致 Fractalkine 的裂解释放，小胶质细胞在内皮损伤的影响下出现了激活的表现，炎症因子表达升高，并且对周细胞造成氧化应激损伤和炎症损伤，我们分别上调和下调 Fractalkine-CX3CR1信号通路评价其对小胶质细胞激活募集的影响以及对糖尿病视网膜微血管病变病程的影响。.本研究认为Fractalkine/CX3CR1信号在高糖诱导微血管内皮细胞损伤后的出现了显著改变，其变化规律及与小胶质细胞激活募集、内层血视网膜屏障破坏之间存在密切关系，MAPK信号家族可能参与了调控小胶质细胞激活募集的细胞内信号途径，本研究初步探讨了视网膜微血管损伤和小胶质细胞失稳态之间的分子机制，为延缓糖尿病视网膜病变的进展开拓治疗新思路。