p38 MAPK信号通路介导高血流阻力脑动静畸形破裂出血机制的研究

Brain arteriovenous malformation (bAVM) is a cerebrovascular disease characterized by intracranial hemorrhage and epilepsy. Previous studies indicated that bAVM hemorrhage was closely related to abnormal hemodynamics, angiogenesis, and inflammation. Our preliminary data have shown 1: high blood flow resistance is a significant risk factor of bAVM hemorrhage. 2. By RNA sequencing, P38 MAPK signaling pathway was identified to be upregulated in the bAVMs with high blood flow resistance. 3. Inflammatory adhesion molecules were upregulated in vascular endothelial cells by hyperactivated P38 MAPK signaling pathway, which also induced weak vascular wall and hemorrhage in zebrafish models. In this proposal, we will: 1. prove that the increased high blood flow resistance can induce hyperactivation of p38 MAPK signaling pathway in mouse models with arteriovenous shunts. 2.clarify the injury mechanism of vascular wall induced by abnormal hyperactivated p38 MAPK signaling pathway in transgenic vascular cell and zebrafish model. 3.test the drug treatment of bAVM by targeting abnormal p38 MAPK pathway, which would provide a theoretical framework for potential clinical therapy.

脑动静脉畸形（bAVM）是一种以颅内出血和癫痫为主要临床表现的脑血管疾病，既往研究显示bAVM的破裂出血与血流动力学、血管生成和炎症密切相关。本课题组的前期研究揭示：1.高血流阻力是bAVM破裂出血的高危因素。2.高血流阻力bAVM出现p38 MAPK信号通路相关基因的异常高表达。3.在血管内皮细胞和斑马鱼模型中，p38 MAPK信号通路的异常激活可以导致炎症粘附因子的过度表达和血管结构不良、破裂出血。本项目拟在前期研究基础上：1.采用大鼠颈动静脉短路模型，验证高血流阻力会导致bAVM血管壁p38 MAPK信号通路的异常激活。2.采用转基因细胞和斑马鱼模型，探讨异常激活的p38 MAPK信号通路引起血管壁损害和破裂出血的机制。3.研究药物抑制异常激活的p38 MAPK信号通路对血管壁的保护作用，为稳定bAVM的药物治疗提供理论基础。

脑动静脉畸形（bAVM）是一种以颅内出血和癫痫为主要临床表现的脑血管疾病，既往研究显示bAVM的破裂出血与血流动力学和炎症密切相关。本项目从前期研究得到提示：bAVM破裂出血与高血流量调控的p38 MAPK信号通路上调密切相关。因此，设计了3部分研究内容：1.建立高血流量的动静脉短路动物模型，通过RNA测序揭示血管壁表达的p38 MAPK炎症相关信号通路与高血流量的关系；2.在血管内皮细胞和平滑肌细胞中上调p38 MAPK信号通路的表达，研究对细胞功能的影响，并进行药物干预，观察对细胞功能的保护作用；3.运用动物模型对p38 MAPK信号通路的作用进行验证，并研究药物干预对高血流损伤血管壁的保护和防治bAVM破裂出血的作用。已完成的研究显示在动静脉短路后1、3、6周，动静脉端出现PI3K、MAPK等多条信号通路的上调，整合素相关基因的表达与MAPK信号通路介导巨噬细胞参与的炎症反应密切相关。细胞实验则显示这些基因调控了血管内皮细胞的增殖与凋亡，并且与血管平滑肌细胞的表型转换、迁移和增殖能力相关。这些结果可以解释高血流量诱发的炎症反应，继而导致血管壁损伤的机制。进一步拟采用KRAS基因体细胞突变小鼠模型验证该机制，并且探讨药物抑制p38 MAPK信号通路诱导的炎症反应对bAVM血管壁的保护作用。该项目的研究贴合临床人类的bAVM疾病模型，将为稳定bAVM的药物治疗提供理论研究基础。