LincRNA-MALAT1抑制内质网应激在抗胰岛纤维化中的作用和机制研究

项目名称： LincRNA-MALAT1抑制内质网应激在抗胰岛纤维化中的作用和机制研究

项目编号： No.81471038

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 黄勤

作者单位： 中国人民解放军第二军医大学

项目金额： 65万元

中文摘要： 胰岛β细胞功能减退在2型糖尿病发生发展中起关键作用，研究提示，胰岛β细胞内质网应激与胰岛组织纤维化形成和β细胞功能减退密切相关。我们的前期研究发现胰岛纤维化在2型糖尿病确诊前就已发生，但机制不清。纤维化是一种慢性炎症状态，促纤维化因子TGF-β与纤维化形成的关系最为密切。我们的研究表明LincRNA-MALAT1对TGFβ刺激的纤维化进程有抑制作用，该作用由B-MYB（一种转录因子）介导，同时B-MYB过表达可抑制糖尿病大鼠胰岛β细胞内质网应激。本课题拟利用转基因小鼠、体外培养的胰岛β细胞及临床标本，以内质网应激为切入点，确定⑴LincRNA-MALAT1通过抑制胰岛β细胞内质网应激进而阻止胰岛纤维化的作用及分子机制；⑵B-MYB在介导LincRNA-MALAT1抑制内质网应激中的作用。研究结果将有助于阐明2型糖尿病发病机制，并为寻找新的药物治疗靶点提供理论依据。

中文关键词： 2型糖尿病；长链非编码RNA-MALAT1；B-MYB；内质网应激；胰岛纤维化

英文摘要： Pancreatic islet β-cell secretion deficiency plays a critical role in the onset and development of type2 diabetes mellitus (T2DM). It is indicated in some studies that endoplasmic reticulum(ER) stress in β cells is closely related to pancreatic islet fibrosis and β-cell dysfunction. Our previous studies demonstrated that pancreatic islet fibrosis took place prior to T2DM. But the mechanisms involved in this phenomenon are still unknown. Fibrosis is a state of chronic inflammation, and TGF-β, a profibrotic factor, is most closely related to such a state. Our study indicated that LincRNA-MALAT1 could inhibit fibrosis stimulated by TGF-β through B-MYB,one of transcription factors. Furthermore, overexpression of B-MYB could inhibit ER stress in pancreatic islet β cells of diabetic rats. The project aimed to experiment on transgenic mice, in vitro cultured pancreatic islet β cells and clinical specimen with a focus on ER stress to ascertain the following: (1) the antifibrotic effect in pancreatic islet exerted by LincRNA-MALAT1 through its inhibition on ER stress in pancreatic islet β cells and the relevant molecular mechanisms; (2) the role of B-MYB in mediating the inhibitory effect of LincRNA-MALAT1 on ER stress. The findings would be conducive to the elucidation of pathogenesis of T2DM, and provide theoretic foundations for novel therapeutic targets for drugs.

英文关键词： Type 2 Diabetes;LincRNA-MALAT1;B-MYB;Endoplasmic Reticulum Stress;Islet Fibrosis