他汀通过CXCR4激活调节T细胞促进颅内淋巴管生成和慢性硬膜下血肿吸收的机制研究

颅内脑膜淋巴系统功能障碍可能与慢性硬膜下血肿（CSDH）形成密切相关。申请人前期通过CSDH动物模型及临床患者研究发现，CSDH外周血、血肿内的调节T细胞（Treg）均降低，他汀可上调其水平进而促血肿吸收；而趋化因子受体CXCR4通路可激活Treg，Treg活化后促进淋巴内皮细胞归巢，进而增强损伤区淋巴管生成。由此，申请人提出：他汀可通过CXCR4激活Treg，Treg发挥促淋巴内皮细胞募集归巢至颅内血肿局部，增强生成淋巴管的功能，加速血肿吸收。本研究拟通过构建CSDH小鼠模型、转基因等方法调控CXCR4及Treg，利用荧光共聚焦、单细胞测序等多种细胞及分子生物学研究方法，确定影响CSDH吸收的CXCR4-Treg关键信号分子通路及效应细胞，分析其与CSDH预后的关系，阐明Treg在他汀促CSDH 吸收中的关键作用及其CXCR4-Treg信号通路，为优化CSDH诊疗提供理论依据及科学循证。

Chronic subdural hematoma (CSDH) is more prevalent in the elderly with a continuously increasing incidence. The intradural lymphatic system has been found and confirmed. It provides the main extracranial drainage channel for intracranial macromolecules clearance. However, the clearance function decreases in the elderly. It is related with the unsuccessful absorption of CSDH. Cooperating with the regulatory T cells (Treg), induces lymphatic endothelial cells to transfer to lymphangiogenesis through modulating the modulate the signal pathways such as CXCR4. Previously, our team has confirmed that Statins regulate Treg and promote the elimination of CSDH. The eliminating path has been proved to be the intracranial lymphatic vessels. We thus hypothesize that the inadequate homing of Treg result in insufficient formation of meningeal lymphatic vessels and then the dysfunction of CSDH drainage. While statins promote homing of Treg via activated by CXCR4 resulting in lymphangiogenesis promotion inside the dura and drainage enhancing.CXCR4 and Treg play a key role in this procedure. The CSDH model will be established in the CXCR4/Treg-activating/inhibiting mouse and statins will be administrated. The role of CXCR4 and.Treg in CSDH formation and absorption will be further determined in vitro and in vivo. The Treg will be selected and pick out from the circulating blood, CSDH and the neomembranes of CSDH repectively. Then the transcriptome sequencing will be performed to determine the key Treg subsets affecting the formation and absorption of CSDH. The relationship between these Treg subsets and the prognosis of CSDH patients will be further analyzed in the circulating blood of CSDH patients. The key Treg subsets as well as the related signal pathways for the formation and absorption of CSDH will be determined, which laid a foundation for optimizing the diagnosis and treatment of CSDH.