microRNA-483 regulation of pancreatic beta-cell function and identity

摘要： 2型糖尿病是一种代谢紊乱，会导致患者的高血糖。功能丧失 β细胞团块是从胰岛素抵抗进展到明显糖尿病的标志。新的 有证据表明，由于β细胞去分化而改变的β细胞的身份被认为是一种 糖尿病中β细胞丢失的新机制。然而，β-细胞去分化的机制 仍有待调查。MicroRNAs(MiRNAs)是调节β- 通过抑制特定靶基因的表达来实现细胞功能和存活。我们发现miR- 483在β-细胞中高表达，在α-细胞中低表达。携带β细胞特异性缺失的小鼠 MIR-483表现出饮食诱导的高血糖和糖耐量下降，但没有改变 以β-细胞团表示。Rna-seq分析显示miR-483失活导致显著增加。 在氧化应激标志物中，包括γ-谷氨酰转移酶(GGT1)，提示miR- 483缺乏会激活氧化应激，从而导致线粒体功能障碍和 同时触发一种适应性抗氧化剂应激反应。值得注意的是，miR-483缺失 增加β细胞不允许基因ALDH1A3的表达，指向一个方向连接 伴随β细胞去分化的microRNAs调节失调。这个项目的目标是识别 启动β细胞去分化的新因子/途径。我们假设miR-483 通过防止β细胞去分化和miR-483失活来维持β细胞的特性 导致抗氧化防御的改变，进而导致线粒体功能障碍。我们会 用以下目标验证这一假设：目的1.确定MIR-483中β细胞的身份 高脂饲料喂养后的虚弱小鼠。目的2.阐明MIR483维持β的机制(S)。 手机身份。此外，miR-483在预防β细胞去分化方面的治疗潜力 将对人类的胰岛进行检查。从这个项目中获得的结果将有助于理解 β细胞去分化的潜在机制和指导糖尿病的治疗。 该项目还将为本科生和研究生提供研究机会。 学生们。

Abstract: Type 2 diabetes is a metabolic disorder that causes hyperglycemia in patients. Loss of functional beta-cell mass is a hallmark of progression from insulin resistance to overt diabetes. New evidence indicated altered identity of β-cells due to beta-cell dedifferentiation is believed to be a new mechanism of β-cell loss in diabetes. However, the mechanism of β-cell dedifferentiation remains to be investigated. microRNAs (miRNAs) are small non-coding RNAs that regulate β- cell function and survival by inhibiting specific target gene expression. We discovered that miR- 483 is highly expressed in β-cells, but much less in α-cells. Mice with β-cell specific deletion of miR-483 exhibited diet-induced hyperglycemia and reduced glucose tolerance without changing in β-cell mass. RNA-seq analysis revealed that miR-483 inactivation resulted in a marked increase in oxidative stress markers including gamma-glutamyltransferase (Ggt1), suggesting that miR- 483 deficiency activates oxidation stress, which causes mitochondrial dysfunction and simultaneously triggers an adaptive antioxidant stress response. Notably, miR-483 deletion increases expression of a β-cell disallowed gene Aldh1a3, pointing to a direction linking dysregulation of microRNAs with β-cell dedifferentiation. The objective of this project is to identity new factors/pathways initiating beta-cell dedifferentiation. We hypothesize that miR-483 maintains β-cell identity by preventing beta-cell dedifferentiation, and miR-483 inactivation induces alteration of antioxidant defense that in turn leads to mitochondrial dysfunction. We will test this hypothesis with the following Aims: Aim 1. Determine the β-cell identity in miR-483 deficient mice after HFD feeding. Aim 2. Elucidate mechanism(s) by which miR-483 maintains β- cell identity. Moreover, the therapeutic potential of miR-483 in preventing β-cell dedifferentiation in human islets will be examined. The results obtained from this project will help understand the underlying mechanisms of β-cell dedifferentiation and guide therapeutical treatments for diabetes. This project will also provide research opportunities for both undergraduate and graduate students.