MODY是单基因突变引起青少年发病的成人型糖尿病，对MODY的精确诊断是MODY精准治疗的难题及关键。申请人前期发现MAPK8IP1(M7V)是一个疑似MODY家系致病性突变，且MAPK8IP1(M7V)突变抗胰岛细胞凋亡作用显著下降，然而其在该病中的作用及机制尚不清楚。由此我们假设MAPK8IP1(M7V)突变与JNK结合能力下降，JNK与c-Jun结合增多，c-Jun磷酸化增强，胰岛β细胞凋亡增加而诱发糖尿病。本项目拟在过表达MAPK8IP1(M7V)细胞模型、MAPK8IP1(M7V)点突变小鼠及该点突变小鼠胰岛β细胞模型，观察MAPK8IP1(M7V)突变对与JNK结合能力、c-Jun磷酸化、细胞凋亡或糖尿病表型的影响，通过CRISPR/Cas9基因编辑技术研究对该点突变进行修复后改善其与JNK结合能力进而改善细胞凋亡的分子机制。阐明该机制，将为该类型MODY的精准治疗提供新策略。

Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes. Accurate diagnosis of MODY is considered challenging but is key for precise treatment of MODY. Our previous results suggested that MAPK8IP1 (M7V) is the pathogenic variant in MAPK8IP1 of a suspected MODY in a Chinese Han family, and the anti-apoptotic effect of MAPK8IP1 (M7V) in pancreatic β-cells was significantly decreased. However, the role and molecular mechanism by which MAPK8IP1 (M7V) causes MODY remain unclear. Therefore, we hypothesized that MAPK8IP1 (M7V) mutation reduces its ability to bind to c-Jun N-terminal kinase (JNK), and increases the amount of JNK that bound to c-Jun, thereby increases the phosphorylation of c-Jun and accelerates the rate of pancreatic β-cell apoptosis, resulting in diabetes. Thus, in this study, we aimed to establish three models of overexpression of MAPK8IP1 (M7V) in INS-1 cells, as well as MAPK8IP1 (M7V) mutations in mouse and pancreatic β-cells derived from the above-mentioned mutant mice. We evaluated the ability of MAPK8IP1 (M7V) mutation to bind to JNK, phosphorylated c-Jun, and the rate of pancreatic β-cell apoptosis and diabetic phenotype. In addition, we studied the molecular mechanism involved to rectify that the point mutation improved the binding ability with JNK and improved β-cell apoptosis by using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/ CRISPR-associated 9 (Cas9) gene editing technology. Unraveling this mechanism of action will provide a novel strategy for precise treatment of this type of MODY.