转录后调控网络在胰岛beta细胞发育和增殖中的功能和机制研究

This study focused on the functions and mechanisms of post-transcriptional regulatory networks in the islet β-cell development and proliferation. Be different from the traditional research of transcription factors and gene function, concern, post-transcriptional regulation has the feathers of high spatial and temporal specificity and dynamics. It's more possible to found therapeutic targets with high specificity and fewer side effects. For the core mechanism of RNA interference, we performed RNA sequencing and expression analysis to first mapped the human the islets lncRNA and miRNA co-expression regulation networks, and used high-throughput RNAi screening method for function study. We established β-cell-specific Tet-On transgenic mouse models and zebrafish models, study the functions of important non-coding RNA (such as mir-221) in the regulatory networks in vivo, and clarify the downstream target genes and pathways. On this basis, we use large serum sample library to explore β-cell function and diabetes-specific miRNA markers. And, by the method of injection of non-coding RNA analogues or inhibitors to diabetic mouse model, we will explore the therapy of post-transcription regulatory intervention for type 2 diabetes. Ultimately, the study will reveal innovative markers and targets for diagnosis and treatment of type 2 diabetes, and new areas of research.

本研究聚焦于转录后调控网络对胰岛β细胞发育和增殖的作用机制。区别于传统领域关注的效应广、特异性低的转录因子和基因功能，转录后调控具有时空特异性高，动态性强等特点，易产生特异性高、副作用小且易干预的治疗靶点。针对核心机制RNA干扰，我们通过RNA测序和表达分析首次绘制了人类胰岛中lncRNA和miRNA的共表达调控网络，并用高通量RNAi筛选的方法研究功能。我们创新性建立了β细胞特异性Tet-On转基因小鼠模型和斑马鱼模型，对转录后调控网络中重要非编码RNA(如mir-221)进行在体功能研究，阐明下游靶基因和通路调控机制。在此基础上，利用大样本血清样本库研究与β细胞功能和糖尿病预后相关的特异性miRNA标志物，并通过对糖尿病模型小鼠进行非编码RNA类似物或抑制剂干预的方法，研究转录后调控网络相关的治疗手段。最终，为诊断和治疗2 型糖尿病提供创新性的标志物和靶点，拓展新的研究领域。

本研究聚焦于转录后调控网络对胰岛β细胞发育和增殖的作用机制。区别于传统领域关注的效应广、特异性低的转录因子和基因功能，转录后调控具有时空特异性高，动态性强等特点，易产生特异性高、副作用小且易干预的治疗靶点。针对核心机制RNA干扰，我们通过RNA测序和表达分析首次绘制了人类胰岛中lncRNA和miRNA的共表达调控网络，并用高通量RNAi筛选的方法研究功能。我们创新性建立了β细胞特异性Tet-On转基因小鼠模型和斑马鱼模型，对转录后调控网络中重要非编码RNA(如mir-221)进行在体功能研究，阐明下游靶基因和通路调控机制。在此基础上，利用大样本血清样本库研究与β细胞功能和糖尿病预后相关的特异性miRNA标志物，并通过对糖尿病模型小鼠进行非编码RNA类似物或抑制剂干预的方法，研究转录后调控网络相关的治疗手段。最终，为诊断和治疗2 型糖尿病提供创新性的标志物和靶点，拓展新的研究领域。