Regulation of Lipid and Lipoprotein Metabolism by Nuclear Receptors
Regulation of Lipid and Lipoprotein Metabolism by Nuclear Receptors
批准号:
9310434
负责人:
Liya Yin
金额:
$39.04万
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-12-01 至 2020-06-30
关键词:
3&apos Untranslated RegionsATP binding cassette transporter 1ATP-Binding Cassette TransportersAdipose tissueAnti-Inflammatory AgentsAnti-inflammatoryAortaApolipoprotein A-IApolipoprotein EArterial Fatty StreakAtherosclerosisCause of DeathCellsCholesterolCholesterol HomeostasisChronicCountryDataDeveloped CountriesDeveloping CountriesDevelopmentDiabetes MellitusDiseaseEmployee StrikesExcretory functionFatty LiverFecesFoam CellsGene ExpressionGenetic TranscriptionHNF4A geneHealthHepaticHigh Density LipoproteinsHigh Fat DietHumanHyperlipidemiaIn VitroInflammationInflammatoryInflammatory ResponseIntestinesKnockout MiceLDL Cholesterol LipoproteinsLeadLipidsLipoproteinsLiverMessenger RNAMetabolicMetabolic stressMetabolismMicroRNAsMusNuclear ReceptorsObesityPharmacologyPlant RootsPlasmaPlayPreventionRNA BindingRegulationRisk FactorsRoleTechniquesTestingTissuesUntranslated RNAatherogenesisbasedisabilityfatty acid oxidationfeedinghypolipidemiain vivolipid metabolismmacrophagenon-alcoholic fatty livernoveloverexpressionpreventreverse cholesterol transporttreatment strategywestern diet
中文摘要
项目摘要
项目概述:动脉粥样硬化性心血管疾病(CVD)是最常见的死亡原因,
发达国家的残疾人。动脉粥样硬化是一种慢性炎症性疾病,
在动脉壁的巨噬细胞中积聚。ATP结合盒(ABC)转运蛋白A1(ABCA 1)和G1
(ABCG 1)是防止巨噬细胞发育成“泡沫”细胞通过促进胆固醇
流出至无脂质的apoA-I或HDL,其随后将巨噬细胞来源的胆固醇递送至肝脏,
肠腔,用于排泄到粪便中。胆固醇流出缺陷导致泡沫形成
巨噬细胞,其被激活以在动脉粥样硬化形成期间促成炎症反应。
微小RNA(miRNAs)是短的非编码RNA,其结合到mRNA的3 'UTR以转录后调节mRNA的表达。
调节基因表达。最近的研究表明,miRNAs是脂质代谢的重要调节因子,
新陈代谢.我们已经产生了miR-34 a基因敲除ApoE基因敲除双敲除(DKO)小鼠。在西方饮食中,
DKO小鼠在主动脉和主动脉根部的动脉粥样硬化病变中具有显著减少,与对照组相比,
ApoE基因敲除小鼠,伴有血浆LDL-C或HDL-C水平不变。进一步的研究表明,
miR-34 a介导的巨噬细胞中Abca 1和Abcg 1的表达显著增加,并对
炎症反应。基于我们的初步研究,我们假设抑制miR-34 a可以保护
通过增加巨噬细胞逆转胆固醇转运和抑制炎症来对抗动脉粥样硬化。到
为了验证这一假设,我们提出了三个具体的目标来确定巨噬细胞miR-34 a是否调节
胆固醇流出和胆固醇逆向转运、炎症和动脉粥样硬化。我们将利用基因
改良的小鼠和药理学操作以及最先进的技术来完成这一过程。
项目完成拟议的研究可能会揭示巨噬细胞miR-34 a在胆固醇中的新作用
miR-34 a可能与代谢、炎症和动脉粥样硬化有关,也可能导致miR-34 a被鉴定为新的靶点。
用于预防和/或消退动脉粥样硬化。
英文摘要
Project Summary
Project Summary: Atherosclerotic cardiovascular diseases (CVD) are the most common causes of death and
disability in the developed countries. Atherosclerosis is a chronic inflammatory disease, characterized by lipid
accumulation in macrophages of arterial walls. ATP-binding cassette (ABC) transporters A1 (ABCA1) and G1
(ABCG1) are essential for preventing macrophages from developing into “foam” cells by promoting cholesterol
efflux to lipid-free apoA-I or HDL, which subsequently delivers macrophage-derived cholesterol to the liver and
intestinal lumen for excretion to the feces. Defective cholesterol efflux leads to formation of foam
macrophages, which are activated to contribute to the inflammatory response during atherogenesis.
MicroRNAs (miRNAs) are short, non-coding RNAs that bind to the 3'UTR of mRNAs to post-transcriptionally
regulate gene expression. Recent studies have documented miRNAs as important regulators of lipid
metabolism. We have generated miR-34aApoe double knockout (DKO) mice. Upon fed a Western diet, the
DKO mice have a marked reduction in atherosclerotic lesions in both the aorta and aortic root as compared to
Apoemice, which is accompanied by unchanged plasma LDL-C or HDL-C levels. Further studies show that
miR-34a macrophages have a striking increase in Abca1 and Abcg1 expression and are protective against
inflammatory response. Based on our preliminary studies, we hypothesize that inhibition of miR-34a protects
against atherosclerosis by increasing macrophage reverse cholesterol transport and inhibiting inflammation. To
test this hypothesis, we propose three specific aims to determine whether macrophage miR-34a regulates
cholesterol efflux and reverse cholesterol transport, inflammation and atherosclerosis. We will use genetically
modified mice and pharmacological manipulations together with state-of-the-art techniques to complete this
project. Completion of the proposed studies may uncover a novel role of macrophage miR-34a in cholesterol
metabolism, inflammation and atherosclerosis, and may also lead to identification of miR-34a as a novel target
for prevention and/or regression of atherosclerosis.
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会议论文
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依托单位:
Regulation of Lipid and Lipoprotein Metabolism by Nuclear Receptors
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批准号:9195921
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项目类别:
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资助金额:$39.04万
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财政年份:2010
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负责人:Liya Yin
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依托单位:
海外基金