A lipid-induced RNA-binding protein in atherosclerosis

动脉粥样硬化中脂质诱导的 RNA 结合蛋白

• 批准号: 10586123
• 负责人: Paul C. Dimayuga
• 金额: $ 46.69万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586123
• 关键词: 3' Untranslated Regions; Ablation; Antisense Oligonucleotides; Arterial Fatty Streak; Atherosclerosis; Binding Sites; Cardiovascular Diseases; Cells; Characteristics; Cholesterol; Cholesterol Homeostasis; Chronic; Data; Development; Diet; Disease; Endoribonucleases; Enzymes; FMR1; Foam Cells; Foamy Macrophage; Fragile X Syndrome; Genes; Genetic; Human; Inflammation; Inflammatory; Inflammatory Response; Inositol; Knowledge; Link; Lipids; Literature; Liver; Macrophage; Mediating; Mental Retardation; Messenger RNA; Methods; MicroRNAs; Motion; Mus; Myelogenous; Neurons; Pathologic; Patients; Phosphorylation; Phosphotransferases; Play; Polyribosomes; Post-Transcriptional Regulation; Protein Deficiency; Protein Inhibition; Proteins; RNA; RNA Stability; RNA-Binding Proteins; RNA-Induced Silencing Complex; Regulation; Reporting; Resolution; Role; Signaling Protein; Sterility; Therapeutic; Transcriptional Regulation; Translations; Vascular Diseases; Work; atherogenesis; autism spectrum disorder; biological adaptation to stress; chemokine; cholesterol transporters; cytokine; endoplasmic reticulum stress; hypercholesterolemia; in vivo; inhibitor; insight; lipid metabolism; novel; novel therapeutics; pharmacologic; posttranscriptional; prevent; protein expression; protein function; reverse cholesterol transport; synaptic function; therapeutic target

PROJECT ABSTRACT Atherosclerosis is a chronic inflammatory vascular disease resulting from maladaptive inflammatory response to an imbalanced lipid metabolism. The cholesterol-laden, foamy macrophages found in plaques play a pivotal role in perpetuating the sterile inflammation that is characteristic of atherosclerosis. Transcriptional control plays a critical role in setting into motion this sterile inflammation. Post-transcriptional mechanisms that operate in atherosclerosis can contribute to resolution of inflammation and promote plaque regression, presenting a therapeutic opportunity. Ribonucleic acid RNA-binding proteins (RBP) alter cytokine and chemokine messenger RNA (mRNA) stability or translation to fine-tune or turn-off the inflammatory response. RBPs also post-transcriptionally regulate key proteins for cholesterol homeostasis and lipid metabolism in macrophages and liver. Despite regulating inflammation, lipid metabolism and cholesterol homeostasis, thereby representing a novel therapeutic opportunity in cardiovascular disease, only a few RBPs and their RNA targets have been directly investigated in atherosclerosis. We made the striking discovery that Fragile X Mental Retardation Protein (FMRP), a widely studied RBP in autism spectrum disorder, is induced by lipids in macrophages and in mouse and human atherosclerotic plaques. We found FMRP associates with and is phosphorylated by the Inositol-Requiring Enzyme-1 (IRE1), a conserved endoplasmic reticulum (ER) stress-sensing kinase/endoribonuclease. ER stress and subsequent IRE1 activation in plaques is causally associated with atherosclerosis. Enhanced IRE1 to FMRP signaling in macrophages may thus promote atherogenesis and represent a novel therapeutic opportunity in atherosclerosis. Our preliminary work shows FMRP inhibition leads to post-transcriptional induction of cholesterol exporters and reduces foam cell formation. Lower cholesterol levels were reported in both FMRP-deficient mice and Fragile X patients, suggesting cholesterol homeostasis is an important target for FMRP. Building on the insight gained through our robust preliminary studies and incorporating additional evidence from literature, we hypothesize that post-transcriptional suppression of cholesterol exporters by the IRE1-phosphorylated FMRP promotes macrophage foam cell formation and atherosclerosis progression. We propose to demonstrate FMRP's role in reverse cholesterol transport, foam cell formation and atherosclerosis in vivo. We will also investigate the consequences of inhibiting IRE1 kinase-mediated FMRP phosphorylation on reverse cholesterol transport, foam cell formation and atherosclerosis in mice. The completion of the proposed studies will illuminate the mechanism of action for this novel IRE1 kinase substrate. The new knowledge gained through these studies could pave the way for the development of effective strategies to prevent atherosclerosis by fine-tuning the homeostatic ER stress response that is pathologically activated by hyerlipidemia.

项目摘要 动脉粥样硬化是一种由适应不良炎症反应引起的慢性炎症性血管疾病 导致脂质代谢失衡。斑块中发现的富含胆固醇的泡沫状巨噬细胞在 在维持动脉粥样硬化特有的无菌炎症中发挥作用。转录控制 在引发这种无菌炎症方面发挥着关键作用。运作的转录后机制 在动脉粥样硬化中可以有助于消退炎症并促进斑块消退，呈现出 治疗机会。核糖核酸 RNA 结合蛋白 (RBP) 改变细胞因子和趋化因子 信使 RNA (mRNA) 稳定性或翻译，以微调或关闭炎症反应。 RBP 还 转录后调节巨噬细胞胆固醇稳态和脂质代谢的关键蛋白 和肝脏。尽管调节炎症、脂质代谢和胆固醇稳态，从而代表 心血管疾病的一种新的治疗机会，只有少数 RBP 及其 RNA 靶点已被研究 直接研究动脉粥样硬化。我们做出了惊人的发现：脆弱 X 智力低下 蛋白质（FMRP）是一种在自闭症谱系障碍中被广泛研究的 RBP，由巨噬细胞和细胞中的脂质诱导。 小鼠和人类动脉粥样硬化斑块。我们发现 FMRP 与 FMRP 相关并被磷酸化 肌醇需求酶-1 (IRE1)，一种保守的内质网 (ER) 应激感应 激酶/内切核糖核酸酶。 ER 应激和随后斑块中 IRE1 的激活与 动脉粥样硬化。巨噬细胞中 IRE1 至 FMRP 信号传导的增强可能会促进动脉粥样硬化形成和 代表了动脉粥样硬化的新治疗机会。我们的初步工作表明 FMRP 抑制 导致胆固醇输出蛋白的转录后诱导并减少泡沫细胞的形成。降低 FMRP 缺陷小鼠和脆性 X 患者均报告了胆固醇水平，表明胆固醇水平 体内平衡是 FMRP 的重要目标。建立在我们通过稳健的初步调查获得的见解的基础上 研究并结合文献中的其他证据，我们假设转录后 IRE1 磷酸化 FMRP 抑制胆固醇输出蛋白促进巨噬细胞泡沫细胞 动脉粥样硬化的形成和进展。我们建议证明 FMRP 在逆转胆固醇方面的作用 体内运输、泡沫细胞形成和动脉粥样硬化。我们也会调查后果 抑制 IRE1 激酶介导的 FMRP 磷酸化对胆固醇反向转运、泡沫细胞形成的影响 和小鼠动脉粥样硬化。拟议研究的完成将阐明作用机制 这种新型 IRE1 激酶底物。通过这些研究获得的新知识可以为 通过微调内稳态内质网应激来制定预防动脉粥样硬化的有效策略 由高脂血症病理激活的反应。