缺氧缺血性脑损伤（HIBD）是人类死亡和致残的主要原因之一，目前缺乏有效的治疗方案，给家庭和社会造成巨大的负担。人类胚胎细胞（hESC）可以在体外无限自我复制，并分化成人体内的各种细胞，包括神经干细胞（NPC）。所以， hESC为HIBD的细胞治疗提供了细胞来源。但是，hESC为基础的细胞治疗最大的瓶颈是移植后的异体免疫排斥。本研究结合前沿的基因编辑技术以及具有人免疫系统的人源化鼠模型，研究hESC衍生组织逃逸免疫排斥反应的机制； 建立与人生理紧密相关的人源化鼠HIBD 的模型，探索hESC衍生NPC移植治疗HIBD的可行性，开发逃逸免疫排斥反应以及加强功能修复的新策略。我们将采用恒河猴胚胎干细胞，在恒河猴中进一步验证人源化鼠模型中发现的免疫耐受策略。我们的研究将阐明移植免疫耐受的机制，并为开发hESC衍生的NPC细胞移植治疗人类HIBD奠定基础。

Hypoxic-ischemic brain damage (HIBD) is one of the leading causes of human immortality and immobility. Without a cure, HIBD imposes serious burdens on the family and society. Human embryonic stem cells (hESC) can undergo unlimited self-renewal and differentiate into all cell types in the body, including neural stem cells/progenitor cells (NPC). Therefore, hESC can serve as the renewable source of NPC to treat HIBD. However, one of the key bottlenecks of the hESC-based therapy is the allogeneic immune rejection of hESC-derived cells. To address this challenge, I propose three aims：(1) To use gene editing technology and humanized mouse model reconstituted with human immune system to investigate the mechanisms to induce immune tolerance of hESC-derived cells. (2) To evaluate the efficacy of immune tolerance strategy in treating humanized HIBD model with allogeneic hESC-derived NPC. (3) To use rhesus monkey model to further investigate the mechanisms of the immune tolerance strategy developed by the humanized mouse model. Our research findings will reveal the immune tolerance pathways and provide the foundation to develop cell therapy of HIBD using hESC-based NPC.