基于Notch信号调控脑缺血后星形胶质细胞活化及其与脑修复关系的影像学研究

Astrocyte in neurovascular unit plays an important and complex intermediate function. Our previous works found that there was close relationship between astrocyte activation and the neurological rehabilitation after cerebral ischemia. This subject aims at the uncertainty for how to promote the neural protection role of astrocyte after cerebral ischemia, and the status of lacking the detection and evaluation systems in vivo. Combining with the latest progress about Notch signaling pathway and transformation of astrocytes, the applicant speculates that regulating Notch signaling can enhance the neural protection mechanism of astrocyte after stroke, improve the brain repair and neural function rehabilitation, and the multiple neuroimaging techniques can be as the living detection and evaluation means. For confirming the hypothesis, we will apply multiple experienced functional neuroimaging techniques, combining the immune-fluorescent staining methods, to state the dynamic evolution of notch signaling and the relationship with the astrocyte activation after cerebral ischemia, reveal the intervention effect of blocking the Notch signaling to the activated astrocyte and the inflammation, neurogenesis, angiogenesis, axonal remodeling and neural function score, provide the secure and efficient evaluating means. This study will push forward the research process of promoting the diverse treatment strategies after cerebral ischemia.

星形胶质细胞在神经血管单元中起到重要且复杂的中间体作用。前期工作发现脑缺血后星形胶质细胞活化与神经功能康复具有密切相关性。本课题针对如何促进缺血后星形胶质细胞神经保护作用的不确定性，和评价体系中活体检测方法相对缺乏的现状，结合有关Notch信号通路与星形胶质细胞激活和转化的最新进展，提出调控Notch信号有利于发挥星形胶质细胞促进缺血脑组织修复和神经功能康复的作用，多模态影像技术能够作为检测和推动实施此干预策略的活体评价手段。为验证该假说，拟采用多种有前期基础的功能影像活体新技术，联合免疫组化荧光染色等方法，阐明脑缺血后Notch信号通路的动态演变规律及其与星形胶质细胞活化的关系，揭示抑制Notch信号干预脑缺血星形胶质细胞活化及其对炎性反应、神经发生、血管生成、神经环路重塑和神经功能状态的影响，提供影像技术做为安全高效活体检测和评价手段的证据，推动多元化治疗脑缺血促进脑修复的研究进程。

本资助项目通过大量实验数据，阐明脑缺血后Notch信号通路的动态变化，揭示星形胶质细胞活化的特点和演变规律，优化调控Notch信号发挥神经保护作用的时机，探明脑缺血后亚急性期抑制Notch1信号能够改变星形胶质细胞活化增殖，抑制炎性反应，促进神经发生和血管生成，整合神经环路，改善功能恢复，从而提供了调节Notch信号促进缺血后脑修复治疗策略的实验基础。同时，本项目实验不断挖掘并充分发挥神经影像学技术优势，将神经病理学方法和影像技术联合印证，建立反映脑缺血后神经血管单元病生理变化、示踪血管生成和神经发生、反映神经传导通路动态变化的动态影像检查体系，为研究脑缺血和促进脑修复干预策略提供一套安全、高效的活体检测和评价手段，并着力于在基础研究和临床应用中架起桥梁，为缺血性脑卒中的防治提供更宽广的治疗时间窗，从而挽救更多的患者，提高其生活质量，因而具有重大的科学意义和实用价值。