SLC30A8主要表达于胰岛β细胞中，该基因编码锌离子转运蛋白ZnT8，其功能缺失能降低人2型糖尿病发病风险，但机制尚不明确。我们利用CRISPR/Cas9基因编辑技术，在人胚胎干细胞中敲除SLC30A8，然后通过体外模拟人胰岛β细胞的发育及功能成熟过程，逐步诱导分化获得具有功能的β细胞。本项目前期研究发现，SLC30A8在人胰岛β细胞功能成熟过程中高表达，其功能缺失可以显著提高胰岛β细胞葡萄糖刺激的胰岛素释放能力。故推测，SLC30A8参与调控人胰岛β细胞功能成熟的过程并调节胰岛素释放。本项目拟利用人胚胎干细胞诱导分化、基因编辑、单细胞RNA测序等技术，阐明SLC30A8在人胰岛β细胞功能成熟过程中的作用，揭示SLC30A8调控葡萄糖刺激胰岛素释放的分子机制。进而通过高通量药物筛选获得能抑制SLC30A8表达而提高胰岛素释放能力的化合物，为糖尿病的防治提供新思路。

SLC30A8 encodes a zinc transporter ZnT8 which is mainly expressed in pancreatic islet β-cells. Loss-of-function mutations of SLC30A8 protect human beings from type 2 diabetes. Nevertheless, the mechanisms underlying this protection have not been elucidated yet. In this project, we used CRISPR/Cas9 genome editing technology to generate SLC30A8 knock-out human embryonic stem cells (hESCs) that were later differentiated into functional human pancreatic β cells by recapitulating β cell development and maturation process via stepwise differentiation. Our preliminary results revealed that SLC30A8 is mainly expressed during β cell maturation process, and glucose-stimulated insulin secretion is significantly enhanced by SLC30A8 loss of function in mature β cells. Thus, we hypothesize that SLC30A8 controls maturation process of β cell and regulates glucose-stimulated insulin secretion. By the application of hESCs differentiation, genome editing and single cell RNA-seq technologies, this project plans to explore the role of SLC30A8 in human β cell maturation process and uncover the molecular mechanism of glucose-stimulated insulin secretion regulated by SLC30A8, and further obtain compound via high throughput screen which can suppress SLC30A8 expression to enhance insulin secretion capacity. This project will provide novel insights for diabetes prevention and treatment.