A lipid-induced RNA-binding protein in atherosclerosis

项目摘要 动脉粥样硬化是一种慢性炎症性血管疾病，由不适应性炎症反应引起。 导致脂类代谢失衡。斑块中发现的富含胆固醇的泡沫巨噬细胞起着关键作用。 在维持动脉粥样硬化特有的无菌炎症方面的作用。转录调控 在启动这种无菌炎症的过程中起着关键作用。转录后机制的运作 在动脉粥样硬化中可以有助于消退炎症和促进斑块消退，呈现一种 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 信使核糖核酸(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 转录后调控巨噬细胞胆固醇稳态和脂类代谢的关键蛋白 还有肝脏。尽管调节炎症、脂质代谢和胆固醇稳态，从而代表 心血管疾病的一个新的治疗机会，只有少数限制性商业惯例及其RNA靶点 直接调查动脉粥样硬化。我们有了一个惊人的发现，脆性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，由巨噬细胞和巨噬细胞中的脂质诱导。 小鼠和人类的动脉粥样硬化斑块。我们发现FMRP与FMRP相关，并被其磷酸化 肌醇需求酶-1(IRE1)--一种保守的内质网应激敏感蛋白 激酶/内切核酸酶。内质网应激和随后斑块中IRE1的激活与 动脉硬化。巨噬细胞中IRE1到FMRP信号的增强因此可能促进动脉粥样硬化的形成和 为动脉粥样硬化提供了新的治疗机会。我们的初步工作显示FMRP抑制 导致转录后诱导胆固醇出口商，并减少泡沫细胞的形成。更低的位置 据报道，FMRP缺陷小鼠和脆性X患者的胆固醇水平都表明胆固醇水平 动态平衡是FMRP的一个重要目标。建立在通过我们强大的初步调查获得的洞察力基础上 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抑制胆固醇输出体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在逆转胆固醇中的作用 体内运输、泡沫细胞形成与动脉粥样硬化。我们还将调查 抑制IRE1激酶介导的FMRP磷酸化对胆固醇逆向转运、泡沫细胞形成的影响 和小鼠的动脉粥样硬化。拟议研究的完成将阐明以下行动机制 这种新型的IRE1激酶底物。通过这些研究获得的新知识可能为 通过微调稳态内质网应激来预防动脉粥样硬化的有效策略的发展 高脂血症引起的病理反应。

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.