颅脑创伤特异的Msr1+小胶质细胞亚群在继发性脑损伤中的作用及其机制研究

脑创伤（TBI）后小胶质细胞持续激活和Aβ沉积是继发损伤及认知障碍的原因之一。本组通过单细胞测序发现：TBI后本该具有Aβ清除功能的Msr1+（巨噬细胞清道夫受体1）小胶质细胞亚群中的Rubicon（Aβ受体回收相关自噬蛋白）却显著下降，提示该亚群Aβ清除功能障碍；且能够募集CD8+T细胞的Cxcl10和Ccl5增高，提示该亚群可促进CD8+T细胞积累，其与创伤后神经变性相关。我们假设TBI引发Msr1+亚群Rubicon相关损伤，致Aβ清除受阻且促Cxcl10和Ccl5表达，使CD8+T细胞积累，共同致TBI神经退行病变发生。本项目①借助TBI小鼠，观察Msr1+亚群和Rubicon表达的动态变化②探明TBI后该亚群Rubicon，Cxcl10和Ccl5改变的分子途径③明确该亚群在Aβ清除和CD8+T细胞积累中的作用。通过研究Msr1+亚群在TBI继发损伤中的作用，为TBI治疗提供新思路

Persistent microglial activation and Aβ deposition after traumatic brain injury (TBI) is one of the cause of secondary brain injury and neurocognitive impairments. Our team finds a contradictory phenomena by ScRNA-seq data analysis: Rubicon(a autophagy protein which is required for recycling of Aβ receptors) in Msr1 (macrophage scavenger receptor 1) expressing microglia subpopulation with function of Aβ clearance is decreased significantly after TBI, it suggests that Msr1+microglia subpopulation have impaired function of Aβ clearance; At the same time, Cxcl10 and Ccl5 which can recruit CD8+T cells are increased in Msr1+microglia subpopulation, it suggests that Msr1+microglia subpopulation can promote activated CD8+T cells accumulation, which is related to chronic neurological/motor impairment. Therefore, it is reasonable to hypothesize that TBI leads to Rubicon-asscociated damage in Msr1+microglia subpopulation, impairing Aβ clearance, and elevating pro-inflammatory cytokine expression, promoting CD8+T cells accumulation, finally, resulting in post-traumatic neurodegeneration. This project is intended to further study①The dynamic change of Msr1+microglia subpopulation and Rubicon expression in TBI mice model②The signaling pathway in Msr1+microglia subpopulation which regulating Rubicon, Cxcl10 and Ccl5 expression after TBI③The role of Msr1+microglia subpopulation in Aβ clearance and CD8+T cells accumulation in TBI mice model. By illustrating the role and mechanism of Msr1+microglia subpopulation in TBI secondary injury, we aim to provide a new idea for TBI treatment