Role of lncRNA Meg3 in obesity-induced endothelial senescence and insulin resistance

lncRNA Meg3在肥胖引起的内皮衰老和胰岛素抵抗中的作用

• 批准号: 10171898
• 负责人: Xinghui Sun
• 金额: $ 48.75万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171898
• 关键词: Aconitate Hydratase; Amyotrophic Lateral Sclerosis; Binding; Binding Proteins; Biochemical; Biological Assay; Blood Vessels; Cardiovascular Diseases; Cell Aging; Cell Cycle Arrest; Chronic Disease; Clinical; Code; Control Groups; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinase Inhibitor 2A; DNA Binding; DNA Damage; Development; Diabetes Mellitus; Disease; Endothelial Cells; Endothelium; Fatty Liver; Gene Expression; Genes; Genus Hippocampus; Glucose; Health; Hepatic; Hepatocyte; Homeostasis; Human; Impairment; In Vitro; Individual; Inflammation Mediators; Insulin; Insulin Resistance; Knock-in Mouse; Knockout Mice; Lead; Leukocytes; Link; Lipids; Liver; Metabolic stress; Mitochondria; Mus; Neurodegenerative Disorders; Obese Mice; Obesity; Oxidative Stress; Pathogenesis; Phenotype; Plasma; Play; Proteins; RNA; RNA-Binding Proteins; Regulation; Risk Factors; Role; Signal Pathway; Specimen; Stimulus; Subgroup; Superoxides; Tamoxifen; Testing; Therapeutic; Tissues; Transcript; Transmission Electron Microscopy; Umbilical vein; Untranslated RNA; Vascular Endothelium; Work; adult obesity; attenuation; beta-Galactosidase; blood glucose regulation; conditional knockout; differential expression; effective therapy; human disease; improved; in vivo; insulin sensitivity; insulin sensitizing drugs; insulin signaling; knock-down; link protein; live cell imaging; matrin 3; mitochondrial dysfunction; obese patients; obese person; oxidation; oxidative damage; paracrine; senescence; transcriptome

PROJECT SUMMARY Obesity-induced insulin resistance is a risk factor for diabetes and cardiovascular disease. To identify new targets for insulin-sensitizing therapies, better understanding of the currently elusive mechanisms behind obesity-induced insulin resistance is needed. Cell senescence is a stable form of cell cycle arrest characterized by several hallmarks, including mitochondrial dysfunction, DNA damage, and senescence-associated secretory phenotype. While cell senescence can exert beneficial effects in human health and disease, it plays a causative role in the pathogenesis of obesity and associated vascular complications. However, the mechanisms underlying endothelial senescence in obesity and how it impacts obesity-induced insulin resistance remain poorly understood. Long non-coding RNAs (lncRNAs) are a subgroup of non-protein coding RNA transcripts that regulate gene expression in a range of signaling pathways, and changes in their expression and function contribute to the pathogenesis of human diseases. To identify lncRNAs that regulate obesity-associated endothelial senescence, transcriptome analysis of mouse vascular endothelium revealed that maternally expressed gene 3 (Meg3) is a top differentially expressed lncRNA upon metabolic stress. Meg3 knockdown causes endothelial senescence in vitro and in obese mice, which is associated with impaired mitochondrial homeostasis and function, and an increase in mitochondrial superoxide. In obese mice, Meg3 knockdown impairs hepatic insulin signaling and induces systemic glucose and insulin intolerance. This preliminary work also identified matrin-3 as a new binding partner of Meg3. Matrin-3 is a DNA- and RNA-binding protein linked to the development of neurodegenerative disorder in humans, a disease closely associated with cardiovascular disease. Matrin-3 knockdown induces oxidative stress and endothelial senescence in vitro. The expression of either Meg3 or matrin-3 positively correlates with the expression of cyclin-dependent kinase inhibitor p16 (an in vivo marker of senescence) in human liver specimens. These observations led to the central hypothesis that endothelial cell senescence contributes to obesity-induced insulin resistance, which is controlled by Meg3 and matrin-3 through the regulation of mitochondrial function. Aim 1 will test the hypothesis that Meg3 and matrin-3 are critical regulators of mitochondrial function in endothelial cells. Aim 2 will determine the role of Meg3 and matrin-3 in endothelial senescence and paracrine function. Aim 3 will test the hypothesis that endothelial senescence contributes to obesity-induced insulin resistance. This project will uncover new roles of Meg3 and matrin-3 in regulating obesity-induced cell senescence in vascular endothelium and their effects on insulin resistance, contributing to the long-term objective to develop more effective therapies for endothelial senescence-related complications of obesity, diabetes, and cardiovascular disease.

项目摘要 肥胖引起的胰岛素抵抗是糖尿病和心血管疾病的危险因素。识别新的 胰岛素敏感疗法的靶标，更好地了解当前难以捉摸的机制 需要肥胖引起的胰岛素抵抗。细胞衰老是一种稳定的细胞周期停滞形式 通过几个标志，包括线粒体功能障碍，DNA损伤和与衰老相关的分泌 表型。虽然细胞衰老可以在人类健康和疾病中产生有益的作用，但它起因于病因 在肥胖和相关血管并发症的发病机理中的作用。但是，基础机制 肥胖症的内皮衰老及其如何影响肥胖引起的胰岛素耐药性仍然很差 理解。长非编码RNA（LNCRNA）是非蛋白质编码RNA转录本的亚组 调节一系列信号通路中的基因表达，并变化其表达和功能 有助于人类疾病的发病机理。识别调节肥胖相关的lncRNA 内皮衰老，小鼠血管内皮的转录组分析表明，母亲 在代谢应激下，表达的基因3（MEG3）是顶级差异表达的lncRNA。 MEG3击倒 导致体外和肥胖小鼠的内皮衰老，这与线粒体受损有关 稳态和功能，以及线粒体超氧化物的增加。在肥胖的老鼠中，MEG3敲除 损害肝胰岛素信号传导并诱导全身葡萄糖和胰岛素不耐症。这项初步工作 还将Matrin-3确定为MEG3的新装订合作伙伴。 Matrin-3是一种与DNA和RNA结合蛋白相关的DNA和RNA结合蛋白 人类神经退行性疾病的发展，这种疾病与心血管密切相关 疾病。 Matrin-3敲低诱导体外诱导氧化应激和内皮衰老。表达 MEG3或Matrin-3与细胞周期蛋白依赖性激酶抑制剂p16的表达呈正相关（AN 人肝标本中的衰老体内标记。这些观察结果导致了一个中心假设，即 内皮细胞衰老有助于肥胖引起的胰岛素抵抗，由MEG3和 Matrin-3通过线粒体功能调节。 AIM 1将检验MEG3和Matrin-3的假设 是内皮细胞中线粒体功能的关键调节剂。 AIM 2将确定MEG3和 内皮衰老和旁分泌功能中的Matrin-3。 AIM 3将检验内皮的假设 衰老有助于肥胖引起的胰岛素抵抗。该项目将揭示MEG3和 在调节血管内皮中肥胖诱导的细胞衰老及其对胰岛素的作用的基质3 抵抗，有助于长期目标开发更有效的内皮疗法 肥胖，糖尿病和心血管疾病的衰老相关并发症。