报告摘要：

Human disease phenotypes associated with haploinsufficient gene requirements are often not recapitulated well in animal models. Human pluripotent stem cells (hPSCs) offer a unique human model for studying human-specific traits. However, the utility of hPSCs has been limited by low efficiency of genome editing. We established an inducible and highly efficient genome editing platform in hPSCs (named iCRISPR). Using this platform coupled with state-of-the-art pancreatic differentiation protocol, we have investigated the association between human GATA6 haploinsufficiency and a wide range of clinical phenotypes that include neonatal and adult-onset diabetes. We found that loss of one GATA6 allele specifically affects the differentiation of human pancreatic progenitors from the early PDX1+ stage to the more mature PDX1+NKX6.1+ stage, leading to impaired formation of glucose-responsive β cells. In addition to this GATA6 haploinsufficiency, we also identified dosage-sensitive requirements for GATA6 and GATA4 in the formation of both definitive endoderm and pancreatic progenitor cells. Our work expands the application of hPSCs from studying the impact of individual gene loci to investigation of multigenic human traits, and it establishes an approach for identifying genetic modifiers of human disease.

报告人简介：

      施中东，安徽寿县人，天津大学本科和硕士，纽约城市大学生物医学工程博士，纽约纪念斯隆凯特琳癌症中心发育生物学博士后。博士期间利用3D培养技术研究血管内壁增生和肿瘤迁移的机械力学信号转导机理。博士后期间从事人诱导多能干细胞体细胞重编程、干细胞定向分化和基因组编辑技术的研究，建立了高效的干细胞基因组编辑技术－iCRISPR平台，并利用此平台进一步建立了研究人胰脏发育和糖尿病致病机理的基于干细胞和基因编辑的模型。目前的工作集中在研究和开发与衰老相关疾病的细胞疗法和基因疗法。在Cell Stem Cell, Cell Reports等杂志发表第一作者和通讯作者论文11篇，论文总引用超过1000次（Google Scholar）。此外还参与编写了4本专业图书。已被邀请和挑选做会议口头报告8次，包括ISSCR meeting, NYSTEM meeting, CFF conference等。目前担任20多个杂志的审稿人。