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慢性炎症性血管疾病，是由于炎症反应的不适应性引起的 导致脂质代谢失衡斑块中富含胆固醇的泡沫状巨噬细胞在 在维持动脉粥样硬化的无菌炎症中的作用。转录控制 在引发这种无菌性炎症中起着关键作用。转录后机制 在动脉粥样硬化中可以有助于炎症的消退和促进斑块消退， 治疗的机会核糖核酸RNA结合蛋白（RBP）改变细胞因子和趋化因子 信使RNA（mRNA）的稳定性或翻译，以微调或关闭炎症反应。限制性商业惯例还 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， 作为心血管疾病的一种新的治疗机会，只有少数RBP及其RNA靶点被 直接研究动脉粥样硬化。我们有了惊人的发现， 蛋白（FMRP）是一种广泛研究的自闭症谱系障碍的RBP，由巨噬细胞和巨噬细胞中的脂质诱导。 小鼠和人动脉粥样硬化斑块。我们发现FMRP与蛋白质结合并被蛋白质磷酸化， 肌醇需要酶-1（IRE 1），一种保守的内质网（ER）应激敏感蛋白 激酶/核糖核酸内切酶。斑块中ER应激和随后的IRE 1激活与以下因素有因果关系： 动脉粥样硬化因此，巨噬细胞中增强的IRE 1至FMRP信号传导可能促进动脉粥样硬化形成， 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形成。低 在FMRP缺陷小鼠和脆性X染色体患者中均报告了胆固醇水平，表明胆固醇 稳态是FMRP重要靶点。基于我们通过强大的初步调查所获得的洞察力， 研究并结合文献中的其他证据，我们假设转录后 通过IRE 1-磷酸化FMRP抑制胆固醇输出细胞促进巨噬细胞泡沫细胞 形成和动脉粥样硬化进展。我们建议证明FMRP的作用，在逆转胆固醇 运输、泡沫细胞形成和动脉粥样硬化。我们还将调查 抑制IRE 1激酶介导的FMRP磷酸化对胆固醇逆向转运、泡沫细胞形成 和小鼠动脉粥样硬化。拟议研究的完成将阐明 这个新的IRE 1激酶底物。通过这些研究获得的新知识可以为 发展有效的策略，通过微调稳态ER应激来预防动脉粥样硬化 由过敏引起的病理性反应。