Fractalkine/CX3CR1调控小胶质细胞极化促进血管性认知障碍髓鞘修复的研究

血管性认知障碍（Vascular Cognitive Impairment，VCI）是位列第二的常见痴呆类型。其病理改变为髓鞘再生障碍导致的脑白质损伤，至今无有效疗法。近期发现小胶质细胞可极化为促炎（M1）与促组织修复（M2）两型。我们前期工作发现，VCI动物中小胶质细胞活化释放炎症因子致髓鞘脱失，但体外实验中小胶质细胞缺失时髓鞘再生障碍。Fractalkine/CX3CR1脑内主要在小胶质细胞上表达, 激活后能活化小胶质细胞。因此我们假设，调节该信号通路促使小胶质细胞的M2型极化，促进髓鞘再生修复，可能是VCI治疗的重要靶点。本课题拟研究如何调控Fractalkine/CX3CR1信号通路，促使小胶质细胞向M2型极化，并阐明极化小胶质细胞对VCI动物模型少突胶质细胞前体细胞增殖、分化、成熟和髓鞘再生的影响，从而实现促进髓鞘修复，改善认知行为的目的，为VCI防治提供新思路和药物作用靶点。

Vascular cognitive impairment (VCI) is the second most common form of dementia. Pathologically VCI features noticeable white matter atrophy resulting from insufficient remyelination. Currently there are no effective treatments. The relation between VCI and inflammation has been highlighted recently. Microglia is the main inflammatory cell type in the central nervous system (CNS). Under different conditions, activated microglia are known to be polarized into M1 and M2 phenotypes and exert dual functions, that is, pro-inflammatory (M1) and tissue repairing (M2) functions. In our previous studies, we found activated microglia can release inflammatory factors resulting in demyelization; however, anti-inflammatory interventions ameliorate the damage and improve the cognitive impairment of VCI animal models. Remyelination is blocked in absence of microglia. Polarization of microglia into M2 has been shown to enhance remyelination. Fractalkine/CX3CR1 is exclusively expressed on microglia in CNS which can regulate injury/repairing respectively. Here we hypothesize that polarization of microglia into M2 is regulated through the Fractalkine/CX3CR1 pathway, and promoting M2 polarization of microglia is a therapeutic strategy for VCI. To test this hypothesis, we propose experiments to systemically determine the effects of polarization of microglia on remyelination. Specifically, we will rigorously examine the role of Fractalkine/CX3CR1 pathway in M2 polarization of microglia, determine the effects of M2 polarization on activation, migration, proliferation and differentiation of oligodendrocyte precursor cells (OPCs), and functional maturation of oligodendrocytes, and investigate behavioral outcomes of promoting remyelination through microglia polarization. Successful completion of the project will provide insights into mechanism of VCI and likely identify the Fractalkine/CX3CR1 pathway as a novel target for development of new drugs for VCI.