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:
- 金额:$ 5万
- 依托单位:
- 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:
- 关键词:ATP binding cassette transporter 1AffectAgonistAnti-Inflammatory AgentsAnti-inflammatoryAntiatherogenicAntiinflammatory EffectApolipoproteins BAreaArterial Fatty StreakArteriesAtherosclerosisAttenuatedBinding SitesBiological AssayBone MarrowCardiovascular systemCause of DeathCellsCessation of lifeCholesterolChromatinConflict (Psychology)DevelopmentDietElementsEnhancersEventGene ExpressionGenesGeneticGenomic approachGenomicsGlassHigh Density LipoproteinsImmunosuppressionIndividualInflammationInflammation MediatorsInflammatoryInflammatory ResponseKnock-outKupffer CellsLaboratoriesLesionLigandsLinkLipidsLipoproteinsLiver X ReceptorLow-Density LipoproteinsMediatingMediator of activation proteinMembrane FluidityModelingMolecularMusMyelogenousMyeloid CellsMyocardial InfarctionNuclearNuclear ReceptorsNucleic Acid Regulatory SequencesOxidesPTGS2 genePathway interactionsPharmacologyPhysiologicalProcessProtein IsoformsPublishingReactionReceptor ActivationRegulationRepressionResearchRiskRoleSequence AnalysisSerumSignal PathwaySignal TransductionSpecificityStrokeSystemTestingTransactivationTranscription Factor AP-1Transcriptional RegulationTransposaseUnited StatesWorkactivator 1 proteinatherogenesisburden of illnesscardiovascular disorder therapyclinical translationexperimental studyfatty acid metabolismgene repressiongenetic manipulationgenome-widein vivoinsightlaser capture microdissectionliver functionmacrophagemortalitymouse modelnovel therapeuticspromoterreceptor bindingreceptor functionreconstitutiontargeted treatmenttranscription factortranscriptome 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
动脉粥样硬化导致心脏病发作和中风,占美国死亡人数的近30%。
动脉粥样硬化是由低密度脂蛋白的内皮下滞留引起的,这导致了一个宏观的,
噬菌体驱动的炎症反应。动脉粥样硬化性心血管疾病(ASCVD)的现有疗法
重点是降低血脂水平,并已有效地减少疾病负担,但实质性的再
治疗个体的副作用风险或心血管事件仍然存在。靶向动脉粥样硬化中的炎症
可能进一步降低ASCVD死亡率,尽管广泛的抗炎治疗可能会导致免疫缺陷的风险。
镇压这项研究的长期目标是阐明可能
形成动脉粥样硬化靶向抗炎治疗的基础,重点是核受体
肝脏X受体(LXR)。氧化胆固醇或药理学激动剂激活LXR可促进胆固醇代谢。
胆固醇流出高密度脂蛋白并抑制炎症。LXR激动剂抑制动脉粥样硬化形成
在小鼠模型中,这种作用与LXR的抗炎功能有关。LXR一直是亲-
通过直接抑制炎症基因的功能或刺激
胆固醇流出,但在动脉粥样硬化中LXR抑制炎症的机制和作用,
尚未最终确定。这里描述的初步研究已经建立了全基因组物种,
在高度特异性的实验系统中,LXR抑制炎症基因的亲和力和遗传要求
避免了过去对这种效应的机制研究中使用的LXR激动剂的脱靶效应。亲-
提出的研究旨在确定炎症因子的分子决定因素和抗动脉粥样硬化作用,
巨噬细胞中LXR的基因抑制。在目标1中,全基因组增强子谱研究将用于
建立参与LXR抗炎作用的基因组元件和转录因子结合位点,
完美。目的2将利用动脉粥样硬化的小鼠模型,这些模型的遗传操作,并将其转基因。
阐明LXR在动脉粥样硬化病变中抑制炎症的潜力的脚本组学测定,
巨噬细胞LXR在LXR激动剂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抗炎功能的机制假说,并支持选择性或
靶向LXR激动剂,可允许LXR的抗动脉粥样硬化活性的临床转化。
项目成果
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