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.

项目概要 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。来识别新的 胰岛素增敏疗法的目标，更好地理解目前难以捉摸的背后机制 肥胖引起的胰岛素抵抗是必要的。细胞衰老是细胞周期停滞的一种稳定形式 具有多种特征，包括线粒体功能障碍、DNA 损伤和衰老相关的分泌 表型。虽然细胞衰老可以对人类健康和疾病产生有益影响，但它也起着致病作用 在肥胖和相关血管并发症的发病机制中的作用。然而，其背后的机制 肥胖引起的内皮衰老及其对肥胖引起的胰岛素抵抗的影响仍然很差 明白了。长非编码 RNA (lncRNA) 是非蛋白质编码 RNA 转录物的一个亚组， 调节一系列信号通路中的基因表达及其表达和功能的变化 有助于人类疾病的发病机制。鉴定调节肥胖相关的 lncRNA 内皮衰老，小鼠血管内皮的转录组分析表明，母体 表达基因 3 (Meg3) 是代谢应激时差异表达最高的 lncRNA。 Meg3 敲低 在体外和肥胖小鼠中引起内皮衰老，这与线粒体受损有关 体内平衡和功能，以及线粒体超氧化物的增加。在肥胖小鼠中，Meg3 敲低 损害肝脏胰岛素信号并诱导全身葡萄糖和胰岛素不耐受。此次前期工作 还确定了 matrin-3 是 Meg3 的新结合伴侣。 Matrin-3 是一种 DNA 和 RNA 结合蛋白，与 人类神经退行性疾病的发展，一种与心血管密切相关的疾病 疾病。 Matrin-3 敲低可在体外诱导氧化应激和内皮衰老。的表达式为 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（一种 衰老的体内标志物）在人类肝脏标本中。这些观察结果得出了一个中心假设： 内皮细胞衰老导致肥胖引起的胰岛素抵抗，这是由 Meg3 和 matrin-3 通过调节线粒体功能。目标 1 将检验 Meg3 和 matrin-3 的假设 是内皮细胞线粒体功能的关键调节因子。目标 2 将确定 Meg3 的作用和 matrin-3 在内皮衰老和旁分泌功能中的作用。目标 3 将检验内皮细胞的假设 衰老会导致肥胖引起的胰岛素抵抗。该项目将揭示 Meg3 和 matrin-3调节肥胖引起的血管内皮细胞衰老及其对胰岛素的影响 耐药性，有助于实现开发更有效的内皮细胞疗法的长期目标 肥胖、糖尿病和心血管疾病等与衰老相关的并发症。