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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：
10170419
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/10170419
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