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Epigenetic Reprogramming in Atherosclerosis

动脉粥样硬化中的表观遗传重编程

基本信息

批准号：
9382567
负责人：
MICHAEL Leo FITZGERALD
金额：
$ 69.05万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9382567
关键词：
Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein E Arterial Fatty Streak Arterial Intimas Atherosclerosis Autoimmune Diseases Bone Marrow Cells Cessation of life ChIP-seq Chemicals Cholesterol Chronic Coronary heart disease Crystallization Cytoplasmic Protein Data Deposition Diet Enzyme Inhibitor Drugs Enzyme Tests Epigenetic Process Fatty acid glycerol esters Genetic Models Genetic Transcription Gout HIV Health Benefit High Density Lipoprotein Cholesterol High Density Lipoproteins Histones Immune Immune response Immune signaling Immunity Immunologic Memory Immunologic Tests Inflammasome Inflammatory Interleukin-1 beta Lead Lipids Low-Density Lipoproteins Mediating Morbidity - disease rate Mus Myelogenous Myeloid Progenitor Cells Nature Outcome Study Pathologic Phagocytes Plasma Public Health Publishing Recruitment Activity Rheumatoid Arthritis Risk Serum Signal Transduction Stem cells Stimulus Systemic Lupus Erythematosus Testing Time Tissues Training Transcription Repressor/Corepressor Viremia XCL1 gene activating transcription factor 3 artery occlusion cardiovascular disorder risk chromatin remodeling coronary artery occlusion cytokine disorder risk feeding granulocyte histone modification hypercholesterolemia low income country macrophage microbial monocyte mortality mouse model new therapeutic target novel patient population pressure progenitor protein complex response transcriptome sequencing western diet

项目摘要

Project Summary/Abstract Epigenetic Reprogramming in Atherosclerosis: Occlusion of coronary arteries by atherosclerotic plaque is the leading cause of mortality and morbidity in the developed world, and is rapidly becoming so in lower income countries, with an estimated 7.4 million deaths globally due to coronary heart disease. Inappropriate lipid deposition in the sub-endothelial arterial space drives plaque progression by the recruitment and differentiation of immune cells, principally monocyte-derived macrophages who attempt to phagocytose these pathologic lipid deposits. Lipid deposition and disease risk is positively correlated with circulating levels of cholesterol carried by low density lipoprotein (LDL). Conversely, higher serum levels of high density lipoprotein (HDL) cholesterol and function associate with decreased risk. We have shown that as LDL derived lipids accumulate and crystallize in the sub-endothelial space and this triggers activation of a large cytoplasmic protein complex termed the NLRP3 inflammasome. This activation triggers subsequent processing and secretion of pro-inflammatory cytokines including IL-1β, that in a feed forward mechanism, recruits more immune cells to the developing plaque. Conversely, and more recently, we have discovered HDL triggers the activity of an anti-inflammatory transcriptional repressor termed ATF3. Most interestingly, we have now also found that Western diet feeding imparts a long-lived immune hyper- responsiveness of bone marrow myeloid progenitors and tissue resident macrophages. Transcriptional profiling using RNA sequencing identified that Western diet feeding induces a primed and hyper-inflammatory state of granulocyte / monocyte progenitors (GMPs) leading to their exacerbated responsiveness towards innate immune activators and their increased proliferation and activation in the bone marrow. In aggregate, our published and preliminary data suggests a hypothesis positing that the pathologic deposition of LDL derived lipid triggers signaling and transcriptional responses that are long lived and are, in part, encoded by an epigenetic reprogramming mechanism in macrophage progenitors and tissue resident macrophages. To explore this hypothesis we propose three specific aims: Aim-1: Define the nature of the long- lived inflammatory signal imparted by the pressure of dietary LDL hypercholesterolemia on macrophage progenitor cells as well as plaque macrophages in mouse models of atherosclerosis. Aim-2: Define if the long- lived hyper-immune state of macrophages is encoded by an epigenetic mechanism and influenced by NLRP3 inflammasome activation. Aim-3: To identify how Western diet induces transcriptional and epigenetic reprogramming of cells.

项目概要/摘要动脉粥样硬化中的表观遗传重编程：动脉粥样硬化斑块阻塞冠状动脉是是发达国家死亡和发病的主要原因，并且在较低国家也迅速变得如此据估计，全球有 740 万人死于冠心病。不当内皮动脉下腔的脂质沉积通过募集和促进斑块进展免疫细胞的分化，主要是单核细胞衍生的巨噬细胞，它们试图吞噬这些细胞病理性脂质沉积。脂质沉积和疾病风险与循环水平呈正相关低密度脂蛋白（LDL）携带胆固醇。相反，高密度脂蛋白的血清水平较高 (HDL) 胆固醇和功能与风险降低相关。我们已经证明，随着低密度脂蛋白衍生的脂质在内皮下空间中积累和结晶，这触发称为 NLRP3 炎症小体的大型细胞质蛋白复合物的激活。此次激活触发促炎细胞因子的后续处理和分泌，包括饲料中的 IL-1β 向前机制，招募更多的免疫细胞到正在发育的斑块中。相反，最近，我们发现 HDL 会触发一种名为 ATF3 的抗炎转录抑制因子的活性。最有趣的是，我们现在还发现西方饮食喂养可以赋予长期的免疫功能亢进。骨髓髓系祖细胞和组织驻留巨噬细胞的反应性。转录谱使用 RNA 测序发现，西方饮食喂养会诱导炎症反应的启动和高炎症状态粒细胞/单核细胞祖细胞 (GMP) 导致其对先天性的反应加剧免疫激活剂及其在骨髓中增加的增殖和激活。总的来说，我们发表的初步数据提出了一个假设，即病理沉积低密度脂蛋白衍生的脂质会触发长期存在的信号传导和转录反应，并且部分地，由巨噬细胞祖细胞和组织驻留物中的表观遗传重编程机制编码巨噬细胞。为了探索这一假设，我们提出了三个具体目标：目标 1：定义长期的本质膳食低密度脂蛋白高胆固醇血症对巨噬细胞的压力传递的活炎症信号动脉粥样硬化小鼠模型中的祖细胞以及斑块巨噬细胞。目标 2：定义是否长巨噬细胞的超免疫状态由表观遗传机制编码并受 NLRP3 影响炎症小体激活。 Aim-3：确定西方饮食如何诱导转录和表观遗传细胞重编程。