The role of Immune-responsive gene 1 and itaconate in atherosclerotic disease

免疫反应基因1和衣康酸在动脉粥样硬化疾病中的作用

基本信息

批准号：
10607641
负责人：
Fazli Kamer Bozal
金额：
$ 5.27万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607641
关键词：
ATF2 gene Aconitic Acid Acute Acute Disease Agonist Anti-Inflammatory Agents Antibodies Aorta Area Arterial Fatty Streak Arteries Atherosclerosis Cardiovascular Diseases Cardiovascular system Cause of Death Cell physiology Cells Cellular Assay Cellular Metabolic Process Cessation of life Cholesterol Chromatin Chronic Citric Acid Cycle Classification Clinical Trials Data Development Economic Burden Environment Enzymes Event FDA approved Failure Gene Expression Regulation Genes IL6 gene Immune Immune Tolerance In Vitro Infection Infiltration Inflammasome Inflammation Inflammation Mediators Inflammatory Interferons Interleukin-1 beta Kinetics LDL Cholesterol Lipoproteins Lesion Ligands Lipids Lipopolysaccharides Low-Density Lipoproteins Macrophage Measures Metabolic Metabolic Pathway Metabolism Modality Modification Mus Myeloid Cells Myocardial Infarction Necrosis Pathogenesis Pathway interactions Peptide Hydrolases Permeability Pharmaceutical Preparations Production Reactive Oxygen Species Regulation Research Residual state Risk Role Sampling Sepsis Stimulus Stroke T-Lymphocyte Testing Therapeutic Therapeutic Effect Thick Thrombosis Time Toll-like receptors Transposase Up-Regulation Wild Type Mouse Work activating transcription factor 3 antimicrobial drug chronic inflammatory disease cytokine extracellular feeding immune activation immunoregulation in vivo indexing inflammatory marker microbial monocyte mouse model neutrophil novel novel therapeutics nuclear factor-erythroid 2 overexpression oxidized low density lipoprotein particle patient subsets prevent recruit single-cell RNA sequencing standard of care systemic inflammatory response targeted treatment transcription factor transcriptome western diet

项目摘要

PROJECT SUMMARY Cardiovascular disease (CVD) is the leading cause of death worldwide and represents a significant economic burden. Atherosclerosis, which is characterized by a build-up of inflammatory lipids and immune cells, is the most common underlying cause of CVD. Early in the pathogenesis of atherosclerosis, LDL-cholesterol particles infiltrate the lining of the artery wall, are modified (e.g., oxidized), and activate inflammatory pathways (e.g., NLRP3 inflammasome) triggering the production of pro-inflammatory cytokines. A failure to resolve inflammation within the artery wall leads to the development of a plaque. The current standard of care includes lipid-lowering drugs such as statins. However, even with successful lipid-lowering, there remains a subset of patients with residual inflammatory risk. These observations led to several large-scale clinical trials (e.g., CANTOS and Lo- DoCo2) that targeted systemic inflammation to treat atherosclerotic CVD. These trials demonstrated that target- ing systemic inflammation reduces adverse cardiovascular events, however, due to an increase in non-cardio- vascular-related deaths, there are currently no FDA-approved anti-inflammatory therapies for atherosclerosis. While targeting inflammation systemically has shown promise, it is important to identify more specific targets and regulators of inflammation within the atherosclerotic plaque to leverage into novel therapies. Research over the past few decades has established that the metabolic state of the immune cell determines its inflammatory ca- pacity. As such, rather than targeting systemic inflammation, we propose to leverage the metabolic regulators of inflammation within the cell. Studies of macrophages stimulated with inflammatory mediators including microbial ligands and cytokines have revealed significant upregulation of the gene Immune-responsive gene 1 (Irg1, also Acod1) and its downstream metabolite itaconate. In addition to being an anti-microbial agent, itaconate controls immune activation and elicits immunological tolerance through (1) regulation of immune cell metabolism, (2) inhibition of late-stage NLRP3 inflammasome activity, and (3) activation of the anti-inflammatory and anti-oxida- tive transcription factors Nuclear factor erythroid 2-related factor 2 and Activating transcription factor 3. While Irg1 and itaconate have been studied in the context of acute inflammation, their role in chronic inflammatory disease, such as atherosclerosis, has not been explored despite sharing many similar pathways. In this proposal, I will define the role of Irg1 and itaconate on immune cell regulation in atherosclerosis, specifi- cally the effects on three major immune cells within the plaque we have found to robustly express Irg1: mono- cytes, macrophages, and neutrophils. Additionally, I will utilize in vivo mouse models of atherosclerosis to test whether IRG1 deficiency exacerbates plaque burden and inflammation. Finally, I will elucidate the utility of 4-OI, a cell-permeable itaconate derivative as a treatment in atherosclerotic CVD. If successful, this will demonstrate for the first time the role of Irg1 and itaconate in chronic inflammation and identify a novel treatment modality for the inflammatory component of atherosclerotic CVD.

项目摘要心血管疾病（CVD）是全球死亡的主要原因，代表着重要的经济负担。动脉粥样硬化的特征是炎症性脂质和免疫细胞的积累，是 CVD最常见的根本原因。在动脉粥样硬化的发病机理的早期，LDL-胆固醇颗粒浸润动脉壁的内壁进行了修饰（例如，氧化），并激活炎症途径（例如， NLRP3炎性体）触发促炎细胞因子的产生。无法解决炎症在动脉壁内导致牙菌斑的发展。当前的护理标准包括降低脂质他汀类药物等药物。但是，即使成功降低脂质，仍有一部分患者残留炎症风险。这些观察结果导致了几项大规模的临床试验（例如，Cantos和Lo- DOCO2）针对全身性炎症来治疗动脉粥样硬化CVD。这些试验表明目标 - 但是，全身性炎症减少了心血管不良事件，由于非心脏的增加与血管相关的死亡，目前尚无针对动脉粥样硬化的FDA批准的抗炎疗法。虽然系统地靶向炎症已经显示出希望，但重要的是要确定更具体的目标和动脉粥样硬化菌斑内炎症的调节剂将其用于新疗法。研究过去的几十年已经确定，免疫细胞的代谢状态决定了其炎症性疾病。能力。因此，我们建议不是针对系统性炎症，而是提议利用细胞内的炎症。对炎症介质（包括微生物）刺激的巨噬细胞的研究配体和细胞因子表明基因免疫反应基因1的显着上调（IRG1，也是 ACOD1）及其下游代谢产物Itaconate。除了是抗微生物剂外，Itaconate控制免疫激活并通过（1）调节免疫细胞代谢，（2）抑制晚期NLRP3炎性体活性，以及（3）激活抗炎和抗氧气 Tive转录因子核因子红系2相关因子2和激活转录因子3。在急性炎症的背景下，对IRG1和Itaconate进行了研究，它们在慢性炎症中的作用尽管共享许多相似的途径，但尚未探讨诸如动脉粥样硬化之类的疾病。在此提案中，我将定义IRG1和Itaconate对免疫细胞调节的作用，在动脉粥样硬化中，特定于 cally对斑块中三个主要免疫细胞的影响，我们发现稳健表达IRG1：单声道细胞，巨噬细胞和中性粒细胞。此外，我将利用动脉粥样硬化的体内小鼠模型进行测试 IRG1缺乏症是否加剧斑块负担和炎症。最后，我将阐明4-OI的效用，在动脉粥样硬化CVD中作为一种可渗透的ITACONATE衍生物作为治疗。如果成功，这将证明 IRG1和Itaconate在慢性炎症中的作用首次确定了一种新颖的治疗方式动脉粥样硬化CVD的炎症成分。