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。

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.