Transcriptional Regulation of Macrophage Function by LXR in Atherosclerosis

动脉粥样硬化中 LXR 对巨噬细胞功能的转录调节

基本信息

批准号：
9754586
负责人：
David G Thomas
金额：
$ 5万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754586
关键词：
ATP binding cassette transporter 1 Affect Agonist Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Antiinflammatory Effect Apolipoproteins B Area Arterial Fatty Streak Arteries Atherosclerosis Attenuated Binding Sites Biological Assay Bone Marrow Cardiovascular system Cause of Death Cells Cessation of life Cholesterol Chromatin Conflict (Psychology)Development Diet Elements Enhancers Event Gene Expression Genes Genetic Genomic approach Genomics Glass High Density Lipoproteins Immunosuppression Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Knock-out Kupffer Cells Laboratories Lesion Ligands Link Lipids Lipoproteins Liver X Receptor Low-Density Lipoproteins Mediating Mediator of activation protein Membrane Fluidity Modeling Molecular Mus Myelogenous Myeloid Cells Myocardial Infarction Nuclear Nuclear Receptors Nucleic Acid Regulatory Sequences Oxides PTGS2 gene Pathway interactions Pharmacology Physiological Process Protein Isoforms Publishing Reaction Receptor Activation Regulation Repression Research Risk Role Sequence Analysis Serum Signal Pathway Signal Transduction Specificity Stroke System Testing Transactivation Transcription Factor AP-1 Transcriptional Regulation Transposase United States Work activator 1 protein atherogenesis burden of illness cardiovascular disorder therapy clinical translation experimental study fatty acid metabolism gene repression genetic manipulation genome-wide in vivo insight laser capture microdissection liver function macrophage mortality mouse model novel therapeutics promoter receptor binding receptor function reconstitution targeted treatment transcription factor transcriptome sequencing

项目摘要

Project Summary Atherosclerosis causes heart attack and stroke and accounts for nearly 30% of deaths in the United States. Atherosclerosis is caused by subendothelial retention of low-density lipoproteins, which leads to a macro- phage-driven inflammatory response. Existing therapies for atherosclerotic cardiovascular disease (ASCVD) focus on lowering serum lipid levels and have been efficacious in reducing disease burden, but substantial re- sidual risk or cardiovascular events in treated individuals remains. Targeting inflammation in atherosclerosis may further reduce ASCVD mortality, although broadly anti-inflammatory therapies may incur a risk of immuno- suppression. The long-term objective of this research is the elucidation of mediators and pathways that may form the basis for targeted anti-inflammatory therapies in atherosclerosis, focusing on the nuclear receptor Liver X Receptor (LXR). Activation of LXR by oxidized cholesterol or pharmacological agonists promotes cho- lesterol efflux to high-density lipoproteins and suppresses inflammation. LXR agonists suppress atherogenesis in mouse models, an effect that has been linked to the anti-inflammatory function of LXR. LXR has been pro- posed to regulate inflammation through either a direct repressive function at inflammatory genes or stimulation of cholesterol efflux, but the mechanism and role of inflammation suppression by LXR in atherosclerosis has not been definitively established. Preliminary studies described here have established the genome-wide speci- ficity and genetic requirements for inflammatory gene repression by LXR in highly specific experimental sys- tems that avoid off-target effects of the LXR agonist used in past mechanistic studies of this effect. The pro- posed research is aimed at defining the molecular determinants and anti-atherogenic effects of inflammatory gene repression by LXR in macrophages. In Aim 1, genome-wide enhancer profiling studies will be used to establish the genomic elements and transcription factor binding sites involved in LXR’s anti-inflammatory ef- fect. Aim 2 will utilize mouse models of atherosclerosis, genetic manipulation of these models, and tran- scriptomic assays to clarify the potential for inflammation suppression by LXR in atherosclerotic lesions and the role of macrophage LXR in anti-atherogenic effects of LXR agonists. This research will reconcile conflicting mechanistic hypotheses about LXR’s anti-inflammatory function and support the development of selective or targeted LXR agonists that may allow clinical translation of LXR’s anti-atherogenic activity.

项目摘要动脉粥样硬化引起心脏病发作和中风，占美国死亡的近30％。动脉粥样硬化是由低密度脂蛋白的下皮下皮保留引起的，这导致了宏噬菌体驱动的炎症反应。动脉粥样硬化心血管疾病（ASCVD）的现有疗法专注于降低血清脂质水平，并有效地降低疾病，但重大的重新被治疗的个体中的胎儿风险或心血管事件仍然存在。靶向动脉粥样硬化的炎症尽管广泛的抗炎疗法可能会引起免疫接种的风险，但可能会进一步降低ASCVD死亡率抑制。这项研究的长期目的是阐明可能的调解人和途径构成动脉粥样硬化中靶向抗炎疗法的基础，重点是核接收器肝X受体（LXR）。通过氧化胆固醇或药物匿名者激活LXR会促进Cho- Lesterol流出对高密度脂蛋白并抑制注射。 LXR激动剂抑制动脉粥样硬化在小鼠模型中，与LXR的抗炎功能有关的效果。 LXR一直在支持摆姿势通过在炎症基因的直接反射功能或刺激来调节炎症胆固醇外排，但LXR在动脉粥样硬化中抑制炎症的机制和作用已有不是确定的。此处描述的初步研究已经确定了全基因组的规格 LXR在高度特定的实验系统中的炎性基因表达的遗传和遗传需求避免在过去的机械研究中使用的LXR激动剂的靶向效应的TEMS。专业人士提出的研究旨在定义炎症的分子决定剂和抗动脉粥样硬化作用 LXR在巨噬细胞中的基因表达。在AIM 1中，全基因组增强子分析研究将用于建立参与LXR抗炎EF-的基因组元素和转录因子结合位点 AIM 2将利用动脉粥样硬化的小鼠模型，对这些模型的遗传操纵以及变形 Scriptomic测定法阐明LXR在动脉粥样硬化病变中抑制注射的潜力和巨噬细胞LXR在LXR激动剂的抗动脉粥样硬化作用中的作用。这项研究将调和冲突关于LXR的抗炎功能的机理假设，并支持选择性或靶向LXR激动剂，可以允许LXR的抗动脉粥样硬化活性进行临床翻译。