内源性竞争性mRNA(ceRNA)具相同的miRNA反应元件(MRE)，可形成一种基于"ceRNA-miRNA对话"的转录组调节网络，参与疾病的发生。目前该领域尚处于概念阶段。糖尿病与炎症有关，但具体机制不很清楚。我们基于前期研究基础，发现炎症与胰岛功能负调控因子有相同的MRE，能与特定的miRNA结合，从而形成ceRNA活动。胰岛炎症时，炎症性ceRNA大量产生，但miRNA池的变化却相对较小。我们推测miRNA池将被炎症性ceRNA耗竭，加强的ceRNA活动势必影响胰岛功能负调控因子的表达，从而介导糖尿病的发生。本项目基于前期研究成果，以点带面，拟研究胰岛细胞炎症时相关ceRNA与miRNA如何开展"网络对话"，胰岛细胞如何通过炎症微环境，继而影响胰岛功能；基于此，最后从细胞和动物水平，探索特定抗炎药物如何降糖的新颖机制，从而为炎症介导糖尿病发病机制的理解及创新药物的研发提供新的思路。

Endogenous and competitive RNAs (ceRNA) bind to miRNA reponse elements (MRE), form a regulatory network across the transcriptome based on cross-talks over ceRNA and miRNA, and mediate the development of diseases. This idea is not well evidenced in the experimental study. Diabetes is mediated by inflammation but the underlying mechanisms are unclear. Based on our preliminary study, we find that both inflammatory factors and negative regulators of insulin have common MRE and may competitively bind to specific miRNA and form ceRNA activities. When pancreatic islet cells are subjected to inflammation stimulation, inflammatory ceRNA will produce largely but miRNA pool will change slightly. It is reasonable for us to suspect that miRNA pool will be exhausted by inflammatory ceRNA "sponge". Following that, enhanced ceRNA activities will promote the expressions of negative regulators of insulin,inhibit the production of insulin and cause the development of diabetes. In this proposal, through case studies, we try to investigate how the "network-talks" are conducted between ceRNA and miRNA in pancreatic islet cells, how the inflammatory micro-environments will affect pancreatic islet functions when these cells are subjected to inflammation stimulation. Finaly, we plan to investigate how the specific anti-inflammatory drugs exert anti-diabetic effects based on the cellular and animal trials. We hope this proposal will give new indications and useful suggestions for understanding pathological mechanisms of diabetes and developing new tactics of anti-diabetic drugs in the future.

本项目主要发现miR-30a通过靶标IL1a，同样对p62，一种参与胰岛素降解的负调控因子，也具有相应靶点，因而开展ceRNA （IL1a-p62）与miR-30a的互作与功能的研究。我们发现miR-30a在炎症刺激的小鼠Raw264.7和Beta-TC-6细胞可以显著抑制IL1a与p62的表达，控制炎症和氧化应激，以及炎性凋亡，保护细胞，在胰岛细胞功能方面，miR-30a还可以上调胰岛素水平，抑制胰岛素负调控因子的水平。而当IL1a-3-UTR和p62转染Raw264.7和Beta-TC-6时，IL1a和p62的表达显著增加，而使用miR-30a抑制剂则取消这种作用，这表明IL1a可能通过ceRNA作用，而影响p62的表达，从而影响胰岛细胞功能。我们在体内实验也发现了类似的现象，而黄芪多糖可能通过抑制IL1a而抑制p62的表达，从而改善胰岛细胞功能。通过该项目我们建立了ceRNA的研究平台，发表SCI论文8篇，培养研究生5名，其中1名学生获得校级优秀硕士论文。