Epigenetic Reprogramming in Atherosclerosis

动脉粥样硬化中的表观遗传重编程

• 批准号: 9914292
• 负责人: MICHAEL Leo FITZGERALD
• 金额: $ 67.36万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914292
• 关键词: Anti-Inflammatory Agents; 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; Gene Expression Profiling; 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; Rheumatoid Arthritis; Risk; Serum; Signal Transduction; Stimulus; Systemic Lupus Erythematosus; Testing; Time; Tissues; Training; Transcription Repressor; Viremia; XCL1 gene; activating transcription factor 3; cardiovascular disorder risk; chromatin remodeling; coronary artery occlusion; cytokine; disorder risk; feeding; granulocyte-monocyte progenitors; histone modification; hypercholesterolemia; low income country; macrophage; microbial; monocyte; mortality; mouse model; new therapeutic target; novel; patient population; pressure; progenitor; protein complex; recruit; response; stem cells; transcriptome sequencing; western diet

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.

项目总结/摘要 动脉粥样硬化的表观遗传重编程：动脉粥样硬化斑块导致冠状动脉闭塞是一种新的机制。 这是发达国家死亡率和发病率的主要原因，在较低的发展中国家， 收入国家，估计全球有740万人死于冠心病。不适当 内皮下动脉间隙中的脂质沉积通过募集和/或微循环驱动斑块进展， 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中的 低密度脂蛋白（LDL）携带的胆固醇。相反，高密度脂蛋白的血清水平越高， (HDL)胆固醇和功能与降低风险有关。 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积聚并结晶，这 触发称为NLRP 3炎性体的大细胞质蛋白复合物的激活。这种激活 触发随后的加工和分泌促炎细胞因子，包括IL-1 β， 前向机制，招募更多的免疫细胞发展斑块。相反，最近，我们 发现HDL触发了一种称为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，西方饮食喂养赋予了一个长寿的免疫超， 骨髓髓样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，西方饮食喂养诱导了一种引发和高度炎症的状态， 粒细胞/单核细胞祖细胞（GMP），导致其对先天性 免疫激活剂及其在骨髓中增加的增殖和激活。 总的来说，我们发表的和初步的数据表明一个假设，即病理性沉积 LDL衍生的脂质触发信号传导和转录反应，这些反应是长期存在的，部分地， 由巨噬细胞祖细胞和组织驻留细胞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：定义长期的性质， 高胆固醇血症对巨噬细胞的压力传递的活性炎症信号 祖细胞以及斑块巨噬细胞在小鼠动脉粥样硬化模型。目标2：确定长期- 巨噬细胞的活性超免疫状态由表观遗传机制编码并受NLRP 3影响 炎性小体激活。目的-3：确定西方饮食如何诱导转录和表观遗传 细胞的重新编程。