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.

项目概要心血管疾病（CVD）是全世界死亡的主要原因，并且代表着重要的经济负担。动脉粥样硬化的特征是炎症脂质和免疫细胞的积聚，是 CVD 最常见的根本原因。在动脉粥样硬化发病机制的早期，低密度脂蛋白胆固醇颗粒渗透动脉壁内壁，被修饰（例如氧化）并激活炎症途径（例如， NLRP3 炎症小体）触发促炎细胞因子的产生。未能解决炎症动脉壁内导致斑块的形成。目前的护理标准包括降脂他汀类药物等药物。然而，即使成功降脂，仍有一小部分患者患有以下疾病：残留炎症风险。这些观察导致了几项大规模的临床试验（例如，CANTOS 和 Lo- DoCo2）针对全身炎症来治疗动脉粥样硬化性心血管疾病。这些试验表明，目标然而，由于非心血管事件的增加，全身性炎症可减少不良心血管事件。与血管相关的死亡，目前尚无 FDA 批准的动脉粥样硬化抗炎疗法。虽然系统性靶向炎症已显示出希望，但重要的是确定更具体的目标和动脉粥样硬化斑块内炎症的调节因子可用于新疗法。研究遍及过去几十年已经确定免疫细胞的代谢状态决定其炎症反应节奏。因此，我们建议利用代谢调节剂，而不是针对全身炎症细胞内的炎症。用包括微生物在内的炎症介质刺激巨噬细胞的研究配体和细胞因子显示免疫反应基因 1（Irg1，也 Acod1) 及其下游代谢物衣康酸。除了作为抗微生物剂外，衣康酸还可以控制通过 (1) 调节免疫细胞代谢，(2) 激活免疫并引发免疫耐受抑制晚期 NLRP3 炎症小体活性，以及 (3) 激活抗炎和抗氧化活性活性转录因子核因子红细胞 2 相关因子 2 和激活转录因子 3。 Irg1 和衣康酸已在急性炎症的背景下进行了研究，以及它们在慢性炎症中的作用尽管有许多相似的途径，但动脉粥样硬化等疾病尚未得到探索。在这个提案中，我将定义 Irg1 和衣康酸在动脉粥样硬化中免疫细胞调节中的作用，具体来说：特别是对斑块内三种主要免疫细胞的影响，我们发现它们强烈表达 Irg1：单- 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来测试 IRG1 缺乏是否会加剧斑块负担和炎症。最后，我将阐明 4-OI 的实用性，一种细胞渗透性衣康酸酯衍生物，用于治疗动脉粥样硬化性 CVD。如果成功的话，这将表明首次研究了 Irg1 和衣康酸在慢性炎症中的作用，并确定了一种新的治疗方式动脉粥样硬化 CVD 的炎症成分。