Macrophage-lipoprotein Interactions

巨噬细胞-脂蛋白相互作用

基本信息

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LDL中胆固醇酯水解的新机制

项目成果

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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:
Intracellular Cholesterol Transport
细胞内胆固醇转运
  • 批准号:
    10059259
  • 财政年份:
    2018
  • 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:
Macrophage-lipoprotein interactions
巨噬细胞-脂蛋白相互作用
  • 批准号:
    7650897
  • 财政年份:
    2009
  • 资助金额:
    $ 43.59万
  • 项目类别:
Macrophage-Lipoprotein Interactions
巨噬细胞-脂蛋白相互作用
  • 批准号:
    10584618
  • 财政年份:
    2009
  • 资助金额:
    $ 43.59万
  • 项目类别:
Macrophage-lipoprotein Interactions
巨噬细胞-脂蛋白相互作用
  • 批准号:
    8185032
  • 财政年份:
    2009
  • 资助金额:
    $ 43.59万
  • 项目类别:
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