CBLB调控小胶质细胞胞葬在蛛网膜下腔出血后神经元细胞焦亡中的作用和机制研究

蛛网膜下腔出血 (SAH) 是严重危害人类健康的疾病，早期脑损伤是其导致神经功能障碍和不良预后的主因。我们的前期研究发现神经元细胞焦亡是SAH后早期脑损伤的重要因素，小胶质细胞胞葬可能是清除细胞焦亡的神经元有效途径，预实验提示泛素化连接酶CBLB可能是调控小胶质细胞胞葬的关键分子，TAM通路在其中可能扮演着重要角色。据此，我们提出假说：SAH后早期脑损伤中小胶质细胞胞葬可清除细胞焦亡的神经元，CBLB通过TAM信号通路调控小胶质细胞胞葬，从而影响SAH后早期脑损伤和神经功能障碍。本课题拟在CBLB条件性敲除小鼠的基础上，应用原代小胶质细胞神经元共培养，活细胞成像，荧光能量共振转移技术，CRISPR/Cas9基因修饰技术，慢病毒载体构建和RNAi靶向调控、MRI扫描等技术阐明CBLB调控小胶质细胞胞葬在SAH后神经元细胞焦亡的作用和机制。本项目的完成将可能为临床治疗SAH提供新的靶点和思路。

Subarachnoid hemorrhage (SAH) is a fatal disease worldwide. Early brain injury is the primary cause of neurological dysfunction and poor prognosis for SAH. Our previous study indicated that neuronal pyroptosis plays an important role in early brain injury. Microglia-mediated efferocytosis may be an effective way to clear the pyroptosis cells. In addition, we found that ubiquitin-ligase enzymes CBLB, as well as TAM pathway, may be a critical factor in the pathological process of pyroptosis. Based on the evidences above, we hypothesize that microglia could attenuates early brain injury and promote neurological function recovery via regulating efferocytosis. The current study was designed to explore the role and mechanism of CBLB-mediated microglia efferocytosis in regulating neuronal pyroptosis after subarachnoid hemorrhage. The completion of this project will provide new targets and strategy for the clinical treatment of SAH.