HK2介导的葡萄糖代谢通路在脑内小胶质细胞发育和功能塑型中的作用

小胶质细胞(microglia, MG)在病灶周围的扩增聚集是多种脑病变中的病理特征，解析其机制对理解和干预疾病进程至关重要。MG源自卵黄囊的原始巨噬细胞，发育早期入脑，在胚胎和新生期迅速增殖，但MG的发育扩增机制不明。项目组以细胞代谢为切入点，通过大数据分析发现，糖代谢关键酶-II型己糖激酶(HK2)特异性表达于MG，在出生后MG富集，在成熟MG下调。利用条件性基因敲除小鼠，项目组发现新生期敲除HK2显著减少脑内MG数量、抑制MG增殖；而成年敲除HK2则无明显影响，提示HK2选择性调控MG的增殖与发育。项目将结合代谢组与高通量测序技术，探究HK2在MG增殖、成熟、吞噬和免疫反应中的作用，解析HK2介导的代谢通路在MG发育和功能塑型中的作用；以急性脑缺血损伤为模型，探究HK2对病变时MG增殖及神经炎症的作用，为解析和干预相关疾病的发病机理提供新的理论基础和分子靶点。

Microglia originate from the primitive macrophages in the yolk sac. They invade the brain at early embryonic stages and rapidly populate the whole brain during development. Microglia reaches the maximal number at postnatal week 2; however, mechanisms underlying the development correlated rapid microglial proliferation remain unknown. We have used high throughput data analysis to examine potential roles of metabolic control in microglial expansion. We found that microglia specifically express the key glycolytic enzyme, hexokinase II (HK2). HK2 is enriched in immature or activated microglia but reduced in mature adult microglia. Selective ablation of HK2 in microglia at postnatal stages substantially attenuated the proliferative capacity of microglia and reduced the number of microglia. However, deletion of HK2 at adult stages had no effects on microglia, suggesting that HK2 may specifically regulate postnatal microglia proliferation during development. Taking advantage of newly-developed cutting-edge techniques, we aim to further unravel the roles of HK2 in microglial proliferation, maturation phagocytosis and immunoresponses, and to illustrate the role of HK2-mediated glucose metabolism in development and functional plasticity of microglia. Since microglia population and clustering are hallmarks of multiple acute brain diseases and injuries, we will set up photo thrombosis-induced acute ischemia models in the mouse brain to further explore the role of HK2 in microglia proliferation and microglia-mediated neuroinflammation under pathological conditions. Our study will provide new insights for understanding the microglial development from a cellular metabolic perspective and present evidence for potential molecular targets for manipulating microglia expansion-related diseases.