RNA-Mediated Inter-Organelle Communication in Atherosclerosis

RNA介导的动脉粥样硬化细胞器间通讯

基本信息

批准号：
10428386
负责人：
Moshe Arditi
金额：
$ 49.89万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10428386
关键词：
Affect Arterial Fatty Streak Arteries Atherosclerosis Automobile Driving Binding Biogenesis Cardiovascular Diseases Cells Chromosome 2 Chronic Communication Coronary Arteriosclerosis Data Development Diabetes Mellitus Disease Dyslipidemias Endoplasmic Reticulum Endoribonucleases Enzymes Epidemic High Density Lipoproteins Human Chromosomes Hyperlipidemia Immune Impairment Inflammation Inflammatory Inositol Insulin Resistance Lead Link Lipids Literature Mediating Membrane Metabolic MicroRNAs Mitochondria Molecular Mus Mutate Nutrient Obesity Organelles Oxidative Stress Pathogenesis Pathologic Pathway interactions Phosphorylation Phosphorylation Site Phosphotransferases Plasma Play Proteins RNA RNA Processing RNA-Binding Proteins RNA-Induced Silencing Complex Regulation Reporting Ribonucleases Role Signal Transduction Site Sterility Stress Substrate Specificity Therapeutic Work atherogenesis base ds RNA-Binding Proteins endonuclease endoplasmic reticulum stress immune activation in vivo insight locked nucleic acid macrophage novel novel therapeutic intervention novel therapeutics operation premature protein kinase R sensor small molecule inhibitor therapeutic target thrombotic

项目摘要

PROJECT ABSTRACT Ischemic cardiovascular disease (CVD) is caused by atherosclerosis, a lipid-driven inflammatory disease affecting the arteries, which can progress into vulnerable plaques and thrombotic occlusion. The precise molecular mechanisms linking nutrient excess and hyperlipidemia to immune activation remains elusive and the discovery of these mechanisms could lead to novel CVD therapeutics. An important primer for inflammation in dyslipidemia is the chronic metabolic overloading and impairment of anabolic and catabolic organelles. Reduction of organelle stress alleviates insulin resistance and atherosclerosis. Recently, we showed that small molecule inhibitors of Inositol-requiring enzyme -1 (IRE1), a proximal ER stress sensor, counteract atherosclerosis progression. The ER membranes also serve as a nucleation site for RNA-induced silencing complex (RISC), and we made the striking discovery that IRE1 kinase phosphorylates the double stranded RNA-binding protein, the protein activator of the protein kinase R (PACT), that associates with RISC. We found lipid stress induces IRE1 to phosphorylate PACT, which suppresses mitochondrial biogenesis (mito-biogenesis), in part by controlling a miRNA (miR)-181c. Homeostatic mechanisms such as mitophagy (to remove) or mito-biogenesis (to replenish) the malfunctioning mitochondria can counteract inflammation and also operate in atherosclerotic plaque cells. Aberrant activation of IRE1-PACT signaling by lipids block mito-biogenesis and propagate mitochondrial oxidative (MOX) stress and inflammation, indicating inhibition of this pathological signaling could counteract atherosclerosis. PACT is proximal to a locus on human chromosome 2 that is linked to premature coronary artery disease and plasma HDL-C levels. PACT expression is induced during atherosclerosis progression and reduced during regression in mice. We hypothesize that suppressing IRE1-PACT signaling will promote mito-biogenesis and counteract inflammation and atherosclerosis. We will elucidate how PACT regulates mito-biogenesis by discovering PACT’s miR target(s) and their RNA targets that are relevant to mito-biogenesis regulation. We discovered miR-181c is one of these PACT targets that blocks mito-biogenesis. We will directly investigate the impact of PACT and miR-181c on hyperlipidemia-induced mito-biogenesis, inflammation and atherosclerosis in vivo. Based on the discovered targets (for miR-181c and others) we will develop a more specific therapeutic targeting approach (using Locked Nucleic Acid-Target-Site Blockers) to ablate miR and target interaction in atherosclerotic mice. The successful completion of these studies will help define an unprecedented mechanism of immune-metabolic crosstalk between ER and mitochondria by which hyperlipidemia can promote MOX stress, inflammation and atherosclerosis. Understanding the intrinsic operation of this RNA-mediated inter-organelle communication during atherogenesis could pave the way for novel therapeutic approaches targeting this specific immune-metabolic cross talk in CVD.

项目摘要缺血性心血管疾病 (CVD) 是由动脉粥样硬化引起的，动脉粥样硬化是一种脂质驱动的炎症性疾病影响动脉，可能发展成易损斑块和血栓闭塞。将营养过剩和高脂血症与免疫激活联系起来的分子机制仍然难以捉摸这些机制的发现可能会成为新的 CVD 治疗方法的重要基础。血脂异常中的炎症是慢性代谢超负荷以及合成代谢和代谢障碍分解代谢细胞器。细胞器应激的减少可减轻胰岛素抵抗和动脉粥样硬化。最近，我们发现肌醇需求酶 -1 (IRE1) 的小分子抑制剂，一种近端 ER 内质网膜也可作为成核位点。对于 RNA 诱导的沉默复合物 (RISC)，我们做出了惊人的发现，IRE1 激酶磷酸化双链 RNA 结合蛋白，即蛋白激酶 R 的蛋白激活剂 (PACT)，与 RISC 相关，我们发现脂质应激会诱导 IRE1 磷酸化 PACT。部分通过控制 miRNA (miR)-181c 来抑制线粒体生物发生 (mito-biogenesis)。稳态机制，例如线粒体自噬（去除）或线粒体生物发生（补充）故障线粒体可以对抗炎症，也可以在动脉粥样硬化斑块细胞的异常激活中发挥作用。脂质对 IRE1-PACT 信号传导的影响阻断线粒体生物发生并传播线粒体氧化 (MOX) 应激和炎症，表明抑制这种病理信号可以对抗动脉粥样硬化。靠近人类 2 号染色体上的一个位点，该位点与过早冠状动脉疾病有关，并且血浆 HDL-C 水平在动脉粥样硬化进展过程中被诱导，并在动脉粥样硬化进展过程中降低。我们发现抑制 IRE1-PACT 信号传导将促进有丝分裂生物发生。我们将阐明 PACT 如何通过调节有丝分裂生物发生。发现 PACT 的 miR 靶点及其与有丝分裂生物发生调控相关的 RNA 靶点。我们发现 miR-181c 是阻断有丝分裂生物发生的 PACT 靶点之一。 PACT 和 miR-181c 对高脂血症诱导的有丝分裂生物发生、炎症和动脉粥样硬化的影响基于发现的靶标（针对 miR-181c 和其他靶标），我们将开发更具体的靶标。治疗靶向方法（使用锁定核酸靶点阻断剂）消除 miR 并靶向这些研究的成功完成将有助于确定动脉粥样硬化小鼠中的相互作用。内质网和线粒体之间前所未有的免疫代谢串扰机制高脂血症可以促进MOX应激、炎症和动脉粥样硬化的内在机制。这种RNA介导的细胞器间通讯在动脉粥样硬化形成过程中的运作可能为动脉粥样硬化形成铺平道路。针对 CVD 中这种特定免疫代谢串扰的新治疗方法的方法。