塞卡病毒（Zika Virus, ZIKV）的新现爆发已经成为全球性的公共卫生事件。ZIKV感染孕妇导致新生儿小头畸形是最严重的疾病表型，也是公众的最大关切，但是其致病的分子机理仍有待进一步研究。在本研究中，借助于我们在人多能干细胞神经靶向分化和基因编辑上的技术优势，我们将建立ZIKV感染人神经前体细胞的体外模型和ZIKV核心致病蛋白在人神经前体细胞中的过表达模型，通过比较ZIKV在前脑背侧（FD）、前脑腹侧（FV）以及后脑和脊髓（H&S）三类神经前体细胞中的毒性表型异同、转录组分析和靶基因干预研究，揭示ZIKV致小头畸形的可能分子机制，并在畸胎瘤和小鼠模型中研究针对分子机制进行干预的神经保护作用。这些针对人源性神经前体细胞的研究将为阐明ZIKV致小头畸形的分子机理，抗小头畸形药物的设计与研发，以及ZIKV疫苗的靶位筛选提供一定的理论依据。

The re-occurrence of Zika virus (ZIKV) infection in many countries renders it a global health emergency recently. The most severe pathology of ZIKV infection is characterized by newborn microcephaly, which is also the major concern of the public. Most importantly, the molecular mechanisms underpinning microcephaly caused by ZIKV prenatal infection remains largely unknown. In this application, based on our well-established systems of neuronal differentiation from human pluripotent stem cells and genetic engineering in human cells, we propose to establish ZIKV infection model and ZIKV pathogenic protein overexpression model in human neuroprogenitor cells. We will systematically compare the microcephaly in vitro disease phenotype in forebrain dorsal neuroprogenitors, forebrain ventral neuroprogenitors and hindbrain and spinal cord neuroprogenitors. Transcriptome profiling will be designed in order to dissect out the underlying molecular mechanisms of microcephaly. Further investigation related to the neuroprotective effects through intervening these identified molecule targets will be performed on teratoma and transgenic mouse model. This study will thus shed new light on the molecular mechanisms of ZIKV related microcephaly and development of anti-ZIKV therapeutic intervention strategies.