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.

项目概要/摘要 超过三分之一的美国成年人肥胖，这使许多人患 2 型肥胖的风险增加 糖尿病和心血管疾病是肥胖症的早期和突出特征。 动脉粥样硬化（一种导致冠状动脉的病理状况）发生和进展的关键步骤 虽然使用他汀类药物治疗动脉粥样硬化已取得进展，但治疗方法尚未取得进展。 解决心血管疾病的残余风险 为了开发更好的治疗方法，有必要阐明。 肥胖相关内皮功能障碍的潜在机制导致风险增加 肥胖相关的动脉粥样硬化。长链非编码 RNA (lncRNA) 的表达和功能的变化。 一类 RNA 转录本，可调节一系列信号通路中的基因表达——有助于 然而，lncRNA 介导的细胞， 肥胖和肥胖相关内皮功能障碍的分子和表观遗传机制 心血管疾病仍然很大程度上未知。 使用 RNA 测序鉴定出许多 lncRNA 在内皮细胞中表达发生显着变化 在这些 lncRNA 中，母系表达的基因 3 (Meg3) 在小鼠和小鼠之间是保守的。 人类，并已显示出在内皮细胞潜在机制中发挥重要作用的特别希望 然而，Meg3 究竟如何影响内皮功能和动脉粥样硬化是未知的。 为了解决这些知识空白，该项目将测试一个中心假设——lncRNA Meg3。 可以通过保护内皮功能响应代谢应激来抑制动脉粥样硬化的发展 – 使用两个特定目标 (SA)：SA1) 确定 Meg3 调节内皮功能的机制和 SA2)确定Meg3敲低是否加速动脉粥样硬化及其相关机制。 将使用一系列方法来确定：1) 介导的信号传导途径以及顺式和反式因子 Meg3 响应代谢应激和 DNA 损伤诱导刺激​​的诱导以及 2) Meg3 的作用 在低密度脂蛋白受体敲除小鼠 SA2 中调节 p53 信号传导和内皮功能。 动脉粥样硬化模型将用于检查改变 Meg3 表达对 p53 信号传导的影响 这项研究将有助于体内内皮功能，包括动脉粥样硬化斑块的形成。 关于 lncRNA Meg3 在肥胖相关内皮功能障碍中的作用的基础知识 动脉粥样硬化，并将有助于孙博士的长期目标，即为制定更好的策略提供信息 通过针对代谢应激诱导的内皮功能障碍来减轻动脉粥样硬化的发展 在未来的工作中，Meg 3 的饮食调节剂将为内布拉斯加州预防中心做出贡献。 通过膳食分子研究肥胖症 (NPOD) 的主题重点是识别生物性肥胖，主要是食源性肥胖 预防、治疗和治愈肥胖及肥胖相关疾病的信号。