以cathepsin B 信号为靶点的自闭症介导神经血管损伤机制及药物调控研究

Autism is a severe neurodevelopmental disorder that manifests as a heterogeneous set of social, cognitive, motor, and perceptual symptoms. Although the etiopathology of autism is not clear, there is increasing evidence that immune system dysfunction which increases in inflammatory cytokines, chemokines, and microglial activity in brain tissue affects many autism patients. By using time-lapse in vivo two-photon laser scanning microscopy, we found leukocyte-endothelial adhesion in autism model mice. We also observed that microglial cells were activated in the cortex of brain and cathepsin B was upregulated in autism model mice. Cathepsin B is known to be involved in inflammatory response and autoimmune response. However, the role of cathepsin B is unclear during autism. In present study, we showed microglial trafficking to sites adjacent to leukocyte adhesion on inflamed cerebral microvessels. In this project, we will investigate the pathophysiological relevance of autism induced leukocyte-endothelial adhesion, microglia activation, neurovascular damage cascade in autism model mice and find the potential new type of drugs for the treatment of autism. In particular, we will define the role of cathepsin B pathway in linking neurovascular inflammation to brain damage and provide a rationale for targeting cathepsin B signaling for neurovascular protection in autism.

自闭症是一种严重的神经发育障碍性疾病，其发病机制尚不清楚。我们前期采用双光子共聚焦活体成像技术结合自闭症小鼠模型开展研究，发现在自闭症小鼠大脑皮层区白细胞-脑血管内皮细胞粘附，白细胞cathepsin B表达特异性增加及小胶质细胞活化。本项目我们将继续开展以下研究：1. 自闭症病理过程中神经血管单元组分的病理变化规律；2. cathepsin B信号通路是否是介导自闭症致脑神经血管损伤病理过程的主要分子机制；3. 以cathepsin B为靶点的基因或药物调控是否是治疗自闭症的有效手段之一；4. 探索是否可以通过以cathepsin B为靶点的小分子化合物筛选，发现高活性的小分子抑制剂，为后续理论研究及药物设计研究提供基础。综上述，通过实施本项目将揭示自闭症中神经血管单元网络变化所带来的病理生理学效应及cathepsin B信号在自闭症发展中的意义，为防治自闭症提供重要的理论和实验依据。

自闭症谱系障碍（ASD）是一种具有社会交往缺陷的神经发育障碍疾病，其发病分子机制尚不清楚。本项目利用双光子激光扫描共聚焦活体检测白细胞粘附动态病理过程，开展了自闭症相关神经血管炎症中白细胞内皮粘附的病理生理机制的研究。研究内容及取得的发现如下：1. 发现了自闭症模型BTBR小鼠脑神经血管单元组分的病理变化规律及其分子机制。2. 探究cathepsin B信号参与BTBR小鼠脑血管炎性病变的病理过程。3. 探讨cathepsin B信号途径调控对自闭症小鼠脑血管中白细胞-内皮细胞粘附等神经炎症的保护作用。4. 探索设计构建了cathepsin B为靶点的小分子化合物，利用高活性的小分子抑制剂进行了相关的细胞及动物实验验证。本项目以脑血管单元为切入点，揭示了cathepsin B在自闭症相关神经血管炎症过程中调节白细胞-内皮细胞粘附的显著作用，为自闭症治疗提供了一种新的途径。