脂代谢紊乱参与脊髓小胶质细胞活化和中枢敏化疼痛机制

脑和脊髓是脂肪组织外含脂类物质最丰富的组织，脂代谢紊乱可以影响中枢神经系统炎症免疫性疾病的进展。小胶质细胞是中枢神经系统的免疫细胞。小胶质细胞的活化在中枢痛觉敏化机制中发挥至关重要的作用。我们推测，脂代谢、小胶质细胞活化、和慢性疼痛存在一定的联系。本研究将采用脂代谢紊乱小鼠（高脂饲养、载脂蛋白基因敲除和肥胖小鼠）来探讨脂代谢紊乱是否激活小胶质细胞和影响疼痛行为。再通过多种体内和体外实验来探讨一个具体的分子机制：脂代谢的中间产物，如胆固醇代谢中间产物二羟甲基戊酸（MVA）和焦磷酸法尼酯(FPP)等，激活Rho/ROCK信号通路，形成以小胶质细胞活化为中心的炎症免疫反应，导致中枢痛觉敏化。本项目提出了一个新的观点，对于慢性疼痛的分子机制及其与全身健康的关系具有重要的理论和临床意义，针对Rho/ROCK通路和相应的脂代谢产物有望成为治疗慢性疼痛的新靶点。降脂药物亦有可能用于慢性疼痛的辅助治疗。

Brain has the highest lipid concentration next to adipose tissue. Deregulated lipid metabolism has been reported to be of particular importance for the central nervous system (CNS) injuries and certain neurological disorders by potentiating immune and inflammatory processes. Microglia are the resident immune cells of CNS and share many immunological characteristics with peripheral macrophage. Microglial activation plays important roles in central sensitization contributing to chronic pain. We hypothesized that deregulated lipid metabolism may also induce spinal microglial activation and contribute to chronic pain. In the present study, firstly we will determine the association of deregulated lipid metabolism with spinal microglial activation and animal pain behaviors by using high-dose lipid diet-induced obese mice, ApoE knockout mice and ob/ob obese mice. Further, we will investigate possible cellular and molecular mechanisms using in vivo/vitro experiments. We supposed that some metabolic intermediates of cholesterol synthesis such as mevalonate (MVA) and isoprenoids such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) may activate spinal microglia by Rho/Rho kinase (ROCK) signaling pathway and involve in the initiation and maintenance of hyperalgesia. Our project presents the novel concept that will help to further understand molecular pain mechanisms scientifically and the relation of chronic pain with other systemic diseases such as lipid metabolic disorders clinically. The specific roles of Rho/ROCK signaling pathway and the deregulated lipid metabolism will open new opportunities for drug development and therapies for chronic pain control. Lipid-lowering drugs may also be tried in controlling chronic pain as well in the future.