小分子介导的细胞重编程脑修复创新研究

The long-term goal of our research is to develop a revolutionary regenerative medicine based on our innovative in vivo astrocyte-to-neuron conversion technology for brain repair. We have recently demonstrated, for the first time, that reactive glial cells induced by brain injury or Alzheimer’s disease (AD) can be directly converted into functional neurons in mouse brain in vivo by overexpression of a single key proneural transcription factor, NeuroD1(Guo et al., Cell Stem Cell, 2014). The impetus for this proposal is based on our latest breakthrough in successfully developing a small molecule-based approach to convert human primary astrocytes into functional neurons in vitro. In our preliminary study, we found that a stepwise combination of small molecules can replace NeuroD1 to reprogram human cortical astrocytes into fully functional neurons in culture (Zhang et al., Cell Stem Cell, 2015). This exciting breakthrough raises the hope for a drug pill-based therapy to regenerate neurons and restore lost/damaged brain function for brain repair. In order to translate these exciting findings into a potential future therapy, this proposal will take a multidisciplinary approach to assess the long-term survival and functional integration of our chemically reprogrammed neurons inside the mouse brain and further develop an efficient stepwise protocol to convert human astrocytes into functional neurons in vivo；moreover, we will evaluate our small molecule-based technology for converting reactive astrocytes into functional neurons in a stroke mouse model.　Given that reactive glial cells are associated with a variety of human diseases caused by brain injury or chronic neurodegeneration, the results from this study will set the stage for future preclinical studies to translate this potential paradigm-shifting technology into regenerative medicine for the treatment of brain injury and neurodegenerative disorders.

修复或再生脑神经细胞是防治脑中风和老年痴呆症等重大脑疾病的关键。本团队在世界上首创基因疗法在体将应激性胶质细胞转化为功能性神经元，开创了脑修复的革新技术。近期，团队又成功地采用小分子化合物诱导方法将人类胶质细胞转化为功能性神经元（Zhang et al., Cell Stem Cell, 2015），为药物再生神经元来治疗脑损伤及神经退行性疾病奠定了基础。本项目中心目标为完善和推广小分子化合物介导的在体转化胶质细胞为功能性神经元核心技术作为脑修复的革新技术；并以小鼠脑中风动物模型为突破口，开发小分子化合物诱导法将脑内胶质细胞转化为功能性神经元来治疗脑中风造成的脑功能丧失。我们预计这一革命性的新技术将在对一系列由脑神经元衰老或死亡引起的神经系统疾病（如老年痴呆症、帕金森氏病及脑中风等）的治疗上具有巨大的应用前景。

修复或再生脑神经细胞是防治脑中风和老年痴呆症等重大脑疾病的关键。项目主持人吴冈义博士曾成功地采用小分子化合物诱导方法将人类胶质细胞转化为功能性神经元（Zhang et al., Cell Stem Cell, 2015），为药物再生神经元来治疗脑损伤及神经退行性疾病奠定了基础。本项目基于前期研究，中心目标为完善小分子化合物介导的在体转化胶质细胞为功能性神经元核心技术作为脑修复的革新技术；并以小鼠脑损伤动物模型为突破口，开发小分子化合物诱导法将脑内胶质细胞转化为功能性神经元来治疗脑组织坏死造成的脑功能丧失。. 本团队利用人类和小鼠星形胶质细胞通过体外筛选，最终发现7个小分子化合物不仅能够将培养的星形胶质细胞重编程为神经元，而且也能够在成年小鼠大脑皮层中用将胶质细胞转化为功能神经元。同时，小分子化合物能够在脑损伤小鼠脑内将病变星形胶质细胞转化神经元并降低炎症等。之后研究团队利用局部中风小鼠模型，基于AAV病毒将神经转录因子NeuroD1将小鼠脑内海马胶质细胞转化为功能神经元,从而修复脑中风造成的脑功能损。.本团队新技术将在对一系列由脑神经元衰老或死亡引起的神经系统疾病（如脑中风、癫痫和阿尔兹海默症等）的治疗上具有巨大的应用前景。