猕猴脑内细胞转化修复局部脑缺血的新颖治疗策略和机制研究

脑中风一直被人们视为难以治愈的重大脑疾病。临床和实验研究长期无法逾越的瓶颈是如何化解脑中风后形成的胶质瘢痕。本项目组前期工作率先在脑损伤和老年痴呆症模型小鼠上，通过转录因子NeuroD1将应激型胶质细胞在大脑内直接转化为神经元，为脑损伤修复提供了开创性思路（Cell Stem Cell, 2014)。近期在非人灵长类动物猕猴上初步建立了血管收缩素Endothelin-1（ET-1）局部脑缺血模型，在猕猴脑损伤部位成功感染了编码NeuroD1的AAV2/9腺相关病毒，初步观察到新生神经元的产生。在此令人振奋的前期工作基础上，本项目拟采用多学科综合技术，包括分子细胞、免疫组化、脑成像、电生理、行为学等技术，深入系统研究猕猴ET-1脑缺血模型中，脑内胶质细胞在体重编程为神经元的转化机制，以及对脑中风的修复。本项目的实施将为治疗人类脑中风，以及其他大脑损伤性疾病提供前所未有的治疗策略和理论基础。

Stroke has long been a major brain disorder difficult to cure. Clinical and experimental studies of stroke have met a bottleneck as how to resolve the glial scar after stroke. Our team member has led a groundbreaking work to reprogram reactive glial cells directly into neurons in the mouse brain with injury or Alzheimer's disease by NeuroD1 transcription factor (Cell Stem Cell, 2014), leading to a novel method to reverse glial scar back to neural tissue. Our recent work successfully established a model of focal cerebral ischemia induced by Endothelin-1 (ET-1) in non-human primate rhesus monkey (macaca mulatta) , and we have successfully infected adeno-associated virus AAV2/9-NeuroD1 into the money’s brain. Our data analysis found newborn neurons in the NeuroD1-infected areas, paving the way for a potential clinical application of this new technology. Based on these exciting preliminary data, we propose to employ multidisciplinary approaches including molecular and cellular, immunohistochemistry, brain imaging, electrophysiological and behavioral techniques to study the mechanism of glia-neuron reprogramming in monkey brain in ET-1 induced cerebral ischemia monkey model. Implementation of this project will provide an unprecedented new strategy for the treatment of stroke and other brain disorders.