2型糖尿病（T2DM）是影响人类健康的重大慢病。多项GWAS研究证实RAS鸟苷酸释放蛋白1（RASGRP1）及其遗传变异与T2DM易感性及胰岛功能相关，但机制未明。本项目前期研究发现：RASGRP1基因多个遗传变异与T2DM治疗预后相关，其中rs55699464多态性可增加RASGRP1的转录活性，可能预期影响转录因子PAX6的结合有关；敲减RASGRP1可抑制胰岛素释放，且RASGRP1与糖转运体GLUT2存在蛋白互作。我们推测rs55699464多态性可能通过促进PAX6与RASGRP1的转录结合，上调GLUT2，促胰岛素分泌，从而延缓T2DM的进程。本项目拟应用CRISPR/Cas9、Duolink-PLA等技术，从细胞、动物及临床三个层面系统阐述PAX6-RASGRP1-GLUT2依赖调控及其多态对胰岛素释放的调控机制、生物学功能及临床意义，为T2DM个体化防治提供新的靶点。

Type 2 diabetes mellitus (T2DM) is a major chronic disease affecting human health. A number of GWAS studies have confirmed that RAS guanyl-releasing protein 1 (RASGRP1) and its genetic variation are significantly associated withs T2DM susceptibility and islet function, but the mechanism has not been elucidated. Our multi-center clinical study found that multiple nucleotide polymorphisms on RASGRP1 gene were associated with the prognosis of T2DM. Luciferase reporter gene confirmed that rs55699464 T allele increased the transcriptional activity of RASGRP1. When RASGRP1 was knocked down, insulin release was reduced. The Co-IP found that RASGRP1 interact with GLUT2. Bioinformatics prediction revealed that the transcription factor PAX6 binds to the region of RASGRP1 gene rs5699464. We speculate that RASGRP1 rs55699464 genetic polymorphism can up-regulate GLUT2, promote the secretion of insulin and delay the process of T2DM by promoting the transcriptional binding of PAX6 and RASGRP1.This project intends to apply CRISPR/Cas9, Duolink-PLA and other technologies to systematically elaborate the regulatory mechanism, biological function and clinical significance of PAX6-RASGRP1-GLUT2 dependence regulation and its polymorphism on insulin release from three levels of cell, animal and clinical, so as to provide a new target for the individualized prevention and treatment of T2DM.