SLC37A4调控糖代谢介导的巨噬细胞胞葬功能在脊髓损伤中的作用及机制研究

持续的炎症微环境是脊髓损伤（SCI）后难以恢复的重要原因。最新研究表明巨噬细胞胞葬功能障碍是许多炎症性疾病的关键发病环节，但其在SCI中的具体作用及相关机制未明。我们前期研究发现SCI3天后巨噬细胞内D-葡萄糖-6-磷酸转运体SLC37A4表达显著下调，而其过表达可增强巨噬细胞胞葬功能并促进SCI小鼠功能恢复。SLC37A4是糖代谢产物转运的重要通道，而糖代谢又是胞葬功能维持正常的主要能量来源。由此我们提出假说：脊髓损伤后SLC37A4下调引起巨噬细胞内糖代谢紊乱从而导致巨噬细胞胞葬障碍并形成炎症微环境，导致SCI难以修复。本项目拟在上述基础上，借助基因条件性过表达小鼠及多种体内外实验技术探讨SLC37A4调控糖代谢介导的巨噬细胞胞葬功能在脊髓损伤中的作用及具体机制；同时将前期已构建完成的靶向基因递送体系用于SLC37A4的递送，为脊髓损伤的研究和治疗提供新的理论基础和实验依据。

Inhibitory inflammatory microenvironment is a critical cause of the failure of spinal cord injury (SCI) recovery. The latest study manifested that defective macrophage efferocytosis underlies a list of inflammatory diseases, but its role in SCI and the specific mechanisms involved are still unclear. Our preliminary experiments revealed that the expression of SLC37A4 (a D-glucose-6-phosphate transporter) in macrophages was down-regulated at 3 days post SCI, while its conditioned overexpression enhanced efferocytosis and functional recovery of SCI mice. SLC37A4 is necessary in glucose metabolism which is indispensable in efferocytosis. Therefore, we hypothesized that the down-regulation of SLC37A4 after SCI led to the disturbance of glucose metabolism, and then defective macrophage efferocytosis, which further resulted in the formation of inflammatory microenvironment and the failure of SCI recovery. This project intends to elucidate the function and specific mechanisms of macrophage efferocytosis mediated by SLC37A4-regulated glucose metabolism in SCI with the help of gene-conditioned overexpression mice and a variety of in vitro and in vivo experiments; besides, a novel gene delivery system precisely targeted at the injured spinal cord has been previously synthesized and will be utilized to deliver SLC37A4, thus providing a new theoretical and experimental basis for the study and therapy of SCI.