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

microRNA-483 对胰腺 β 细胞功能和身份的调节

• 批准号: 10580237
• 负责人: Xiaoqing Tang
• 金额: $ 40.43万
• 依托单位: MICHIGAN TECHNOLOGICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580237
• 关键词: Address; Alpha Cell; Antioxidants; Avena sativa; Beta Cell; Biochemistry; CYP2E1 gene; Cell Death; Cell Differentiation process; Cell Survival; Cell physiology; Cells; Clinical; Data; Development; Diabetes Mellitus; Diet; Down-Regulation; Education; Eligibility Determination; Endocrine; Enzymes; Exhibits; Failure; Funding; Gamma-glutamyl transferase; Gene Expression; Genes; Glucagon; Goals; High Fat Diet; Human; Hyperglycemia; Impairment; Institution; Insulin; Insulin Resistance; Laboratories; Link; Metabolic Diseases; Metabolic stress; Michigan; MicroRNAs; Mitochondria; Molecular Biology; Mus; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Pathway interactions; Patients; Physiology; Process; Regulation; Reporter; Research; Research Infrastructure; Role; Science; Stress; Structure of beta Cell of islet; System; Technology; Testing; Therapeutic; Universities; Untranslated RNA; Up-Regulation; biological adaptation to stress; cell dedifferentiation; cell type; diabetes mellitus therapy; diabetes pathogenesis; diabetic; feeding; functional loss; glucose tolerance; graduate student; insight; islet; mid-career faculty; mitochondrial dysfunction; novel; novel therapeutic intervention; oxidation; prevent; progenitor; programs; transcription factor; transcriptome sequencing; transdifferentiation; treatment strategy; undergraduate student

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.

摘要： 2型糖尿病是一种代谢紊乱，导致患者高血糖症。丧失功能性 β-细胞质量是从胰岛素抵抗发展到明显糖尿病的标志。新 有证据表明，由于β细胞去分化而导致的β细胞身份改变被认为是一种 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）是一类小的非编码RNA， 通过抑制特定靶基因的表达来提高细胞功能和存活率。我们发现miR- 483在β细胞中高度表达，但在α细胞中表达较少。具有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葡萄糖耐量降低，而不改变 在β细胞团中。RNA-seq分析显示，miR-483失活导致细胞凋亡显著增加。 包括γ-谷氨酰转移酶（Ggt 1）在内的氧化应激标志物，表明miR- 483缺乏激活氧化应激，导致线粒体功能障碍， 同时触发了适应性抗氧化应激反应。值得注意的是，miR-483缺失 增加β细胞不允许的基因Aldh 1a 3的表达，指向一个方向， 微RNA的失调与β细胞去分化。本项目的目标是识别 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 诱导抗氧化防御的改变，进而导致线粒体功能障碍。我们将 用以下目标来检验这个假设：目标1。确定miR-483中的β细胞身份 缺陷型小鼠后HFD喂养。目标2.阐明miR-483维持β- 细胞识别此外，miR-483在预防β细胞去分化中的治疗潜力是潜在的。 在人类胰岛中的作用。从这个项目中获得的结果将有助于了解 β细胞去分化的潜在机制，并指导糖尿病的治疗性治疗。 这个项目也将为本科生和研究生提供研究机会 学生