Macrophage-lipoprotein Interactions
巨噬细胞-脂蛋白相互作用
基本信息
- 批准号:9384099
- 负责人:
- 金额:$ 43.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-01 至 2021-04-30
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAGFG1 geneAcid LipaseActinsArterial Fatty StreakAtherosclerosisBiological AssayBiological ProcessBlood VesselsBone MarrowBone Marrow TransplantationCell Culture TechniquesCell membraneCellsChelating AgentsCholesterolCholesterol EstersCyclodextrinsDefectDendritic CellsDepositionElectron MicroscopyEnzymesExcisionF-ActinFemaleFilipinFluorescence MicroscopyFoam CellsFunctional disorderGenesGoalsHigh Density Lipoprotein CholesterolHigh Density LipoproteinsHydrolysisImmune systemIonsKnock-outKnockout MiceLabelLeadLesionLipidsLipoproteinsLow Density Lipoprotein ReceptorLow-Density LipoproteinsLysosomesMacrophage Cell BiologyMediatingMethodsMicroscopyMolecularMorphologyMusOpticsPGRN genePhagocytesPharmacologyPolymersProcessProductionProteinsPublishingRNA InterferenceResolutionRoleSNAP receptorSYK geneScanning Electron MicroscopySignal TransductionSignaling MoleculeSiteStructureSynapsesTLR4 geneTherapeutic InterventionTranscriptional ActivationWild Type MouseWorkatherogenesisbasebeta-Cyclodextrinsextracellularimprovedin vivoknock-downlow density lipoprotein inhibitormacrophagemalemicroscopic imagingmonocytemouse modelmultiphoton imagingnovelnovel therapeutic interventionnovel therapeuticspolymerizationresponsesealtooltranscriptome sequencing
项目摘要
We described a novel mechanism for the hydrolysis of cholesteryl esters in retained and aggregated LDL
(agLDL), which is the predominant form of lipoprotein in atherosclerotic lesions. Macrophages (MΦ) create
tightly sealed compartments that surround the agLDL. They acidify these compartments and secrete
lysosomal enzymes into them, creating a lysosomal synapse. This leads to formation of unesterified
cholesterol outside the cell, which can be delivered to the plasma membrane leading to changes in signal
transduction and foam cell formation. We hypothesize that this mechanism for degrading agLDL has
significant differences compared to phagocytic or endocytic mechanisms and that these differences have
important consequences for the pathophysiology and treatment of atherosclerosis. We will study the cellular
mechanisms that regulate this process (which we call exophagy); better characterize exophagy in vivo; and
explore a novel role for HDL and cyclodextrins in clearing the cholesterol produced by exophagy. (1)
Characterize the mechanisms for extracellular hydrolysis of agLDL. We have used MΦ from knockout mice,
RNAi, and pharmacological agents to identify a role for TLR4, Myd88, SYK, Akt, PI3 kinases, and other
signaling molecules in exophagy. We use three main quantitative assays: lysosome secretion, formation of F-
actin where MΦ contact agLDL, and formation of lipid droplets. We will identify the Rab and SNARE proteins
required for lysosome secretion, and we will identify genes that are activated during exophagy. (2) Determine
the role of lysosomal synapses in atherosclerotic lesions. We will use optical and electron microscopy to
analyze the activity of lysosomal synapses in mouse models of atherosclerosis. We will use bone marrow
transplants into LDL receptor knockout mice to determine the importance of signaling processes. (3)
Characterize HDL interactions with agLDL in contact with MΦ. AgLDL in contact with MΦ has very high levels
of unesterified cholesterol. HDL or cholesterol-balanced cyclodextrins can remove excess cholesterol with no
loss of cholesterol from cells. We will characterize this process and its impact on foam cell formation.
我们描述了保留和聚集的 LDL 中胆固醇酯水解的新机制
(agLDL),它是动脉粥样硬化病变中脂蛋白的主要形式。巨噬细胞 (MΦ) 产生
围绕 agLDL 的密封隔室。它们酸化这些隔室并分泌
溶酶体酶进入其中,形成溶酶体突触。这导致形成未酯化的
细胞外的胆固醇,可以传递到质膜,导致信号变化
转导和泡沫细胞形成。我们假设这种降解 agLDL 的机制
与吞噬或内吞机制相比存在显着差异,并且这些差异
对动脉粥样硬化的病理生理学和治疗产生重要影响。我们将研究细胞
调节这一过程的机制(我们称之为外食);更好地表征体内外食;和
探索 HDL 和环糊精在清除外食产生的胆固醇方面的新作用。 (1)
描述 agLDL 细胞外水解的机制。我们使用了来自基因敲除小鼠的 MΦ,
RNAi 和药物制剂,用于确定 TLR4、Myd88、SYK、Akt、PI3 激酶和其他药物的作用
外食中的信号分子。我们使用三种主要的定量分析:溶酶体分泌、F-形成
肌动蛋白,其中MΦ接触agLDL,并形成脂滴。我们将鉴定 Rab 和 SNARE 蛋白
溶酶体分泌所需的,我们将鉴定在外噬过程中被激活的基因。 (2)确定
溶酶体突触在动脉粥样硬化病变中的作用。我们将使用光学和电子显微镜
分析动脉粥样硬化小鼠模型中溶酶体突触的活性。我们将使用骨髓
移植到 LDL 受体敲除小鼠中以确定信号传导过程的重要性。 (3)
表征 HDL 与 agLDL 与 MΦ 接触的相互作用。与 MΦ 接触的 AgLDL 水平非常高
未酯化的胆固醇。 HDL 或胆固醇平衡环糊精可以去除多余的胆固醇,且无需
细胞中胆固醇的损失。我们将描述这个过程及其对泡沫细胞形成的影响。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Frederick R. Maxfield其他文献
Endocytic recycling
内吞再循环
- DOI:
10.1038/nrm1315 - 发表时间:
2004-02-01 - 期刊:
- 影响因子:90.200
- 作者:
Frederick R. Maxfield;Timothy E. McGraw - 通讯作者:
Timothy E. McGraw
Role of cholesterol and lipid organization in disease
胆固醇和脂质组织在疾病中的作用
- DOI:
10.1038/nature04399 - 发表时间:
2005-11-30 - 期刊:
- 影响因子:48.500
- 作者:
Frederick R. Maxfield;Ira Tabas - 通讯作者:
Ira Tabas
Optical non-invasive detection of Niemann-Pick disease in vitro and in vivo
- DOI:
10.1016/j.ymgme.2016.11.166 - 发表时间:
2017-01-01 - 期刊:
- 影响因子:
- 作者:
Prakrit V. Jena;Thomas V. Galassi;Daniel Roxbury;Robert E. Schwartz;Frederick R. Maxfield;Daniel A. Heller - 通讯作者:
Daniel A. Heller
Intracellular Calcium and Calcineurin Regulate Neutrophil Motility on Vitronectin Through a Receptor Identified by Antibodies to Integrins αv and β3
- DOI:
10.1182/blood.v87.5.2038.2038 - 发表时间:
1996-03-01 - 期刊:
- 影响因子:
- 作者:
Bill Hendey;Moira Lawson;Eugene E. Marcantonio;Frederick R. Maxfield - 通讯作者:
Frederick R. Maxfield
Microglia degrade Alzheimer’s amyloid-beta deposits extracellularly via digestive exophagy
- DOI:
10.1016/j.celrep.2024.115052 - 发表时间:
2024-12-24 - 期刊:
- 影响因子:
- 作者:
Rudy G. Jacquet;Fernando González Ibáñez;Katherine Picard;Lucy Funes;Mohammadparsa Khakpour;Gunnar K. Gouras;Marie-Ève Tremblay;Frederick R. Maxfield;Santiago Solé-Domènech - 通讯作者:
Santiago Solé-Domènech
Frederick R. Maxfield的其他文献
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{{ truncateString('Frederick R. Maxfield', 18)}}的其他基金
Role of microglial lysosomes in amyloid-A-beta degradation
小胶质细胞溶酶体在淀粉样蛋白-A-β降解中的作用
- 批准号:
10734289 - 财政年份:2023
- 资助金额:
$ 43.59万 - 项目类别:
Histone Deacetylase Inhibitors for Treatment of Niemann-Pick C1 Disease
组蛋白脱乙酰酶抑制剂用于治疗 Niemann-Pick C1 病
- 批准号:
9986392 - 财政年份:2015
- 资助金额:
$ 43.59万 - 项目类别:
Histone Deacetylase Inhibitors for Treatment of Niemann-Pick C1 Disease
组蛋白脱乙酰酶抑制剂用于治疗 Niemann-Pick C1 病
- 批准号:
9333438 - 财政年份:2015
- 资助金额:
$ 43.59万 - 项目类别:
A Phase 1 Dose Escalation Study of Vorinostat in Niemann-Pick C1 Disease
伏立诺他治疗尼曼-匹克 C1 病的 1 期剂量递增研究
- 批准号:
8639788 - 财政年份:2014
- 资助金额:
$ 43.59万 - 项目类别:
A JEM 1400 Electron Microscope for a Core Facility
用于核心设施的 JEM 1400 电子显微镜
- 批准号:
7793743 - 财政年份:2010
- 资助金额:
$ 43.59万 - 项目类别:
A multiphoton microscope for translational and basic biomedical research
用于转化和基础生物医学研究的多光子显微镜
- 批准号:
7842170 - 财政年份:2010
- 资助金额:
$ 43.59万 - 项目类别:














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