胰岛素样生长因子结合蛋白1的表观遗传调控在２型糖尿病发病中的机制研究

项目名称： 胰岛素样生长因子结合蛋白1的表观遗传调控在２型糖尿病发病中的机制研究

项目编号： No.81500612

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 顾天伟

作者单位： 南京大学

项目金额： 18万元

中文摘要： 血清胰岛素样生长因子结合蛋白1（IGFBP1）是衡量个体胰岛素分泌水平及胰岛素敏感性的标记物。早期研究提示IGFBP1表达水平主要受到环境因素的影响。在2型糖尿病中，表观遗传变化介导基因和环境的相互作用进而导致疾病的发生发展。我们前期研究发现IGFBP1基因5’非翻译区的甲基化水平在2型糖尿病患者中显著升高，而血清IGFBP1水平则明显降低，提示IGFBP1水平在2型糖尿病中受到表观遗传调控，但其具体机制尚不明确。本研究拟利用病例-对照及随访的人群样本及细胞实验，研究IGFBP1启动子区域在2型糖尿病中DNA甲基化水平的变化，探讨调控其甲基化的因素及其相关机制，明确DNA甲基化对其基因启动子活性的影响，从而有助于寻找2型糖尿病新的表观遗传标记物，用于预测疾病的发展，并为早期干预治疗靶点提供理论基础。

中文关键词： 2型糖尿病；遗传学；表观遗传学；DNA甲基化；胰岛素样生长因子结合蛋白1

英文摘要： Circulating insulin-like growth factor binding protein 1 (IGFBP1) is a biomarker of insulin secretion and insulin sensitivity. Previous study indicated that the environment factors predominate for the IGFBP1 levels. There is a growing body of evidences suggesting a role for epigenetic modifications in the complex interplay between genes and environment in type 2 diabetes. Our previous study has demonstrated that the DNA methylation levels in the 5’UTR of IGFBP1 was increased in type 2 diabetes patients, whereas the circulating levels were decreased, suggesting us the IGFBP1 levels were regulated by epigenetic factors in type 2 diabetes. However, the molecular mechanism is still unclear. Therefore, in current study we proposed to investigate the alteration of DNA methylation levels in the promoter of IGFBP1 in type 2 diabetes with a prospective case-control cohort study and cell-line experiments, to further explore the underlying mechanism, and to identify the effects of DNA methylation on the gene promoter activity. It may help us to search for the novel epigenetic marker, which is used for prediction of type 2 diabetes and providing fundamental knowledge for early intervention.

英文关键词： type 2 diabetes;genetics;epigenetics;DNA methylation;IGFBP1