IL4/TREM2介导小胶质/巨噬细胞吞噬功能在糖尿病脑出血中的作用及机制研究

脑出血性卒中是影响人民生命健康的重大高危疾病，而合并糖尿病的卒中患者病情更重、预后更差。申请人前期发现，高血糖通过抑制小胶质/巨噬细胞吞噬功能减缓脑内血肿清除，可能是加重脑出血损伤的关键。进一步发现，TREM2，一种参与调节小胶质细胞吞噬功能的膜受体，在糖尿病脑出血小鼠的小胶质/巨噬细胞中被显著下调；有研究提示IL4激活巨噬细胞膜上的TREM2受体表达。据此我们提出假说：高血糖在脑出血后通过抑制小胶质/巨噬细胞TREM2信号从而减弱其吞噬功能，延缓血肿清除，加重神经功能缺损；IL4可通过激活TREM2信号改善小胶质/巨噬细胞吞噬功能，保护神经功能。本课题拟采用活体双光子成像、慢病毒感染、流式细胞术等手段，结合基因敲除小鼠和人体标本，阐明TREM2在糖尿病合并脑出血中的作用及机制，为其治疗提供新策略。

Intracerebral hemorrhage is a devastating disease. The patients with diabetes are more serious with worse prognosis. Our preliminary experiments indicated that high glucose could slow down the clearance of intracerebral hematoma by suppressing phagocytic function of microglia/macrophage, which might aggravate the severity of brain damage. Further experiment found, TREM2, a kind of membrane receptor regulating microglia/macrophage function, was suppressed in hyperglycemic intracerebral hemorrhage mice. IL4 was found up-regulating TREM2 expression in macrophage. Based on these data, we proposed a hypothesis that hyperglycemia could suppress microglia/macrophage phagocytic function after intracerebral hemorrhage by TREM2 signal, thus slowing down the clearance of hematoma and alleviate brain damage; IL4 could improve microglia/macrophage phagocytic function and protect brain function by enhancing TREM2 signal. This study aims to illustrate the role and mechanism of TREM2 in hyperglycemic intracerebral hemorrhage both in mice and patients, with two-photon imaging, lentivirus, flow cytometry, knockout mice, etc. This study may provide a new strategy to treat brain injury after hyperglycemic intracerebral hemorrhage.