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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的： 2 型糖尿病是一种代谢性疾病，会导致患者出现高血糖。 β细胞质量是从胰岛素抵抗进展为明显糖尿病的标志。有证据表明，由于 β 细胞去分化而导致 β 细胞身份的改变被认为是糖尿病中β细胞丢失的新机制然而，β细胞去分化的机制。 microRNA (miRNA) 是调节 β-的小非编码 RNA。我们发现，miR-通过抑制特定靶基因的表达来实现细胞功能和存活。 483 在 β 细胞中高度表达，但在 β 细胞特异性缺失的 α 细胞中表达较少。 miR-483 在不改变的情况下表现出饮食诱导的高血糖和糖耐量降低 RNA-seq 分析显示 miR-483 失活导致 β 细胞质量显着增加。氧化应激标志物，包括γ-谷氨酰转移酶（Ggt1），表明 miR- 483 缺乏症会激活氧化应激，导致线粒体功能障碍同时触发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 Aldh1a3 的表达，指向连接的方向 β 细胞去分化引起的 microRNA 失调该项目的目的是鉴定。我们突袭了 miR-483 启动β细胞去分化的新因子/途径。通过防止 β 细胞去分化和 miR-483 失活来维持 β 细胞身份诱导抗氧化防御的改变，进而导致线粒体功能障碍。通过以下目标检验该假设：目标 1. 确定 miR-483 中的 β 细胞身份 HFD 喂养后有缺陷的小鼠目标 2. 阐明 miR-483 维持 β- 的机制。此外，miR-483 在预防 β 细胞去分化方面的治疗潜力。将在人类胰岛中进行检查，该项目获得的结果将有助于理解。 β细胞去分化的潜在机制并指导糖尿病的治疗。该项目还将为本科生和研究生提供研究机会学生。