Long noncoding RNA, obesity-associated endothelial dysfunction, and atherosclerosis

长链非编码RNA、肥胖相关内皮功能障碍和动脉粥样硬化

• 批准号: 9795741
• 负责人: Xinghui Sun
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9795741
• 关键词: Address; Affect; Antisense Oligonucleotides; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Attenuated; Bioinformatics; Biological; Biological Assay; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Communication; Cell Proliferation; Cells; ChIP-seq; Chemicals; Code; Coronary Arteriosclerosis; DNA; DNA Damage; Development; Diet; Disease; Economic Burden; Endothelial Cells; Endothelium; Epigenetic Process; Feedback; Functional disorder; Future; Gene Expression; Genes; Genetic Transcription; Goals; Health; Healthcare; Heart Hypertrophy; Hormones; Human; In Vitro; Individual; Knockout Mice; Knowledge; Lead; Low Density Lipoprotein Receptor; Mediating; Metabolic stress; Methods; Modeling; Molecular; Molecular Cloning; Mus; Mutagenesis; Nebraska; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated cardiovascular disease; Obesity associated disease; Pathogenesis; Pathologic; Play; RNA; Regulation; Research; Residual state; Risk; Role; Signal Pathway; Signal Transduction; Stimulus; TP53 gene; Testing; The Sun; Transcript; Untranslated RNA; Vascular Endothelium; Work; adult obesity; cardiovascular disorder risk; endothelial dysfunction; foodborne; human disease; in vivo; insight; insulin signaling; interest; knock-down; liver injury; loss of function; macrophage; mouse model; next generation sequencing; obesity prevention; obesity risk; prevent; response; transcription factor; transcriptome; transcriptome sequencing; tumor

PROJECT SUMMARY/ABSTRACT More than one-third of U.S. adults are obese, which predisposes many people to an increased risk of type 2 diabetes and cardiovascular disease. Endothelial dysfunction is an early and prominent feature in obesity and a critical step in the initiation and progression of atherosclerosis, a pathological condition resulting in coronary artery disease. While progress has been made in treating atherosclerosis by use of statins, treatments have not addressed the residual risk of cardiovascular disease. To develop better treatments, there is a need to elucidate the underlying mechanisms of obesity-associated endothelial dysfunction that contribute to increased risk for obesity-related atherosclerosis. Changes in the expression and function of long non-coding RNAs (lncRNAs) – a class of RNA transcripts that regulate gene expression in a range of signaling pathways – contribute to the pathogenesis of obesity-related diseases via various mechanisms. However, lncRNA-mediated cellular, molecular, and epigenetic mechanisms underlying endothelial dysfunction in obesity and obesity-associated cardiovascular disease remain largely unknown. A preliminary transcriptome analysis of mouse vascular endothelium using RNA-sequencing identified many lncRNAs with significant changes in expression following metabolic stress. Among these lncRNAs, maternally expressed gene 3 (Meg3) is conserved between mice and humans and has shown particular promise in playing an essential role in the mechanisms underlying endothelial dysfunction and atherosclerosis. However, exactly how Meg3 affects endothelial function and atherosclerosis is unknown. To address these gaps in knowledge, this project will test a central hypothesis – that lncRNA Meg3 can inhibit the development of atherosclerosis by protecting endothelial function in response to metabolic stress – using two specific aims (SAs): SA1) identify the mechanism by which Meg3 regulates endothelial function and SA2) determine whether Meg3 knockdown accelerates atherosclerosis and its related mechanisms. In SA1, an array of methods will be used to determine: 1) the signaling pathway and cis- and trans-factor(s) that mediate the induction of Meg3 in response to metabolic stress and DNA damage-inducing stimuli and 2) the role of Meg3 in regulating p53 signaling and endothelial function. In SA2, a low-density lipoprotein receptor knockout mouse model of atherosclerosis will be used to examine the effects of altering Meg3 expression on p53 signaling and endothelial function in vivo, including the formation of atherosclerotic plaques. This research will contribute fundamental knowledge about the role of lncRNA Meg3 in obesity-associated endothelial dysfunction and atherosclerosis and will contribute to Dr. Sun's long-term goal to inform the development of better strategies to attenuate the development of atherosclerosis by targeting metabolic stress-induced endothelial dysfunction in obesity. In future work the dietary regulators of Meg 3 will contribute to the Nebraska Center for the Prevention of Obesity through Dietary Molecules (NPOD)'s thematic focus of identifying biological, primarily food-borne signals that prevent, treat, and cure obesity and obesity-related diseases.

项目摘要/摘要 超过三分之一的美国成年人肥胖，这使许多人遭受2型的风险增加 糖尿病和心血管疾病。内皮功能障碍是肥胖和 动脉粥样硬化的启动和进展的关键步骤，这是导致冠状动脉的病理状况 动脉疾病。尽管通过使用他汀类药物在治疗动脉粥样硬化方面取得了进展，但尚未治疗 解决了心血管疾病的残留风险。为了开发更好的治疗，需要阐明 肥胖相关内皮功能障碍的基本机制导致了增加的风险 与肥胖有关的动脉粥样硬化。长期非编码RNA（LNCRNA）的表达和功能的变化 - 一类RNA转录本在一系列信号通路中调节基因表达 - 有助于 肥胖相关疾病的发病机理通过各种机制。然而，lncRNA介导的细胞， 肥胖和肥胖相关的内皮功能障碍的分子和表观遗传机制 心血管疾病在很大程度上尚不清楚。小鼠血管的初步转录组分析 使用RNA测序的内皮鉴定了许多LNCRNA，表达显着变化。 代谢压力。在这些lncRNA中，母体表达的基因3（meg3）在小鼠和 人类，在内皮的基础机制中发挥重要作用，表现出特别的希望 功能障碍和动脉粥样硬化。但是，MEG3准确地影响内皮功能和动脉粥样硬化是 未知。为了解决知识中的这些差距，该项目将检验一个中心假设 - lncrna meg3 可以通过保护代谢应激来保护内皮功能来抑制动脉粥样硬化的发展 - 使用两个特定目标（SAS）：SA1）确定MEG3调节内皮功能和 SA2）确定MEG3敲低是否加速了动脉粥样硬化及其相关机制。在sa1中，一个 方法阵列将用于确定：1）介导的信号通路以及顺式和跨因素 MEG3响应代谢应激和DNA损伤诱导的刺激和2）MEG3的作用 在调节p53信号传导和内皮功能方面。在SA2中，低密度脂蛋白受体基因敲除小鼠 动脉粥样硬化模型将用于检查改变MEG3表达对p53信号传导和 体内内皮功能，包括动脉粥样硬化斑块的形成。这项研究将做出贡献 关于lncRNA MEG3在肥胖相关内皮功能障碍和 动脉粥样硬化，并将为Sun博士的长期目标做出贡献，以告知更好的策略 通过靶向代谢应激诱导的内皮功能障碍的动脉粥样硬化的发展 肥胖。在未来的工作中 通过饮食分子（NPOD）识别生物学，原代食物的主题重点 预防，治疗和治愈肥胖和与肥胖相关疾病的信号。