Macrophage Cell-Surface Proteolysis and Inflammation

巨噬细胞表面蛋白水解和炎症

基本信息

  • 批准号:
    7140029
  • 负责人:
  • 金额:
    $ 24.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2005
  • 资助国家:
    美国
  • 起止时间:
    2005-12-01 至 2010-11-30
  • 项目状态:
    已结题

项目摘要

Numerous studies examining atherosclerotic lesions from human and animal models have established the central role of the macrophage in atherosclerosis. Despite these observations, it is still unclear how the multiple pro- and anti-inflammatory capabilities of the macrophage are balanced within lesions. One potentially important mechanism for them to regulate their function is by the rapid modulation of the repertoire of proteins expressed on their cell surface through proteolytic "shedding". In addition to dynamically altering the cell surface constituents, shedding also leads to the release of soluble ectodomains with distinct biological properties. This proposal will focus on the ADAM family of proteases that have gained recognition as primary effectors of ectodomain shedding. Early lesions of atherosclerosis are characterized by lipid-filled macrophages. Scavenger receptors are responsible for this massive accumulation of cholesterol, and their significance for atherogenesis is highlighted by multiple gene knockout studies. Fas ligand (FasL) is a key cell surface regulator of macrophage apoptosis and activation. Both scavenger receptors and FasL can be proteolytically cleaved from the cell surface resulting in down-regulated cellular expression. The release of soluble scavenger receptor can inhibit foam cell formation in vitro and in vivo, while FasL is proteolytically released in both active and inactive forms. Thus, proteolytic shedding of scavenger receptors and FasL could modulate lesion initiation and progression. However, the enzymes responsible for their shedding have not been fully characterized. In Aim 1, we will determine the proteases involved in the shedding of scavenger receptors and FasL, and the functional significance of shedding on atherogenesis will be examined in Aim 4 by expressing uncleavable mutants of these substrates. In addition to possible effects on lesion initiation, ectodomain shedding may also contribute to lesion progression and plaque rupture. Macrophage activation induces the shedding a multitude of inflammatory mediators, and ADAM17 has been shown to be responsible for the shedding of several of these. In Aim 4, we will test the role of ADAM17 in lesion initiation, progression and plaque rupture by genetically modulating its expression in macrophages. In addition, proteomic approaches will be utilized to identify novel substrates for ADAM17 potentially involved in atherosclerosis (Aim 2), and to determine the role played by oxidants in regulating the activity of this enzyme (Aim 3) in collaboration with Project 4.
许多研究从人类和动物模型检查动脉粥样硬化病变

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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Elaine W Raines其他文献

Nogo puts the brake on vascular lesions
Nogo 阻止血管损伤
  • DOI:
    10.1038/nm0404-348
  • 发表时间:
    2004-04-01
  • 期刊:
  • 影响因子:
    50.000
  • 作者:
    Elaine W Raines
  • 通讯作者:
    Elaine W Raines

Elaine W Raines的其他文献

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{{ truncateString('Elaine W Raines', 18)}}的其他基金

Proteolytic control of local inflammatory macrophage proliferation
局部炎症巨噬细胞增殖的蛋白水解控制
  • 批准号:
    9038435
  • 财政年份:
    2015
  • 资助金额:
    $ 24.16万
  • 项目类别:
Proteolytic control of local inflammatory macrophage proliferation
局部炎症巨噬细胞增殖的蛋白水解控制
  • 批准号:
    8892773
  • 财政年份:
    2015
  • 资助金额:
    $ 24.16万
  • 项目类别:
Cloaking Key MMP-9 Substrates to Probe the role of Their Cleavage in Plaque Ruptu
隐藏关键 MMP-9 底物以探究其裂解在斑块破裂中的作用
  • 批准号:
    8055931
  • 财政年份:
    2010
  • 资助金额:
    $ 24.16万
  • 项目类别:
Cloaking Key MMP-9 Substrates to Probe the role of Their Cleavage in Plaque Ruptu
隐藏关键 MMP-9 底物以探究其裂解在斑块破裂中的作用
  • 批准号:
    7872152
  • 财政年份:
    2010
  • 资助金额:
    $ 24.16万
  • 项目类别:
Core--Mouse Atherosclerosis and Analysis
核心--小鼠动脉粥样硬化及分析
  • 批准号:
    7140041
  • 财政年份:
    2005
  • 资助金额:
    $ 24.16万
  • 项目类别:
MACROPHAGE CELL-SURFACE PROTEOLYSIS IN ATHEROGENESIS
动脉粥样硬化形成中的巨噬细胞表面蛋白水解
  • 批准号:
    6861526
  • 财政年份:
    2005
  • 资助金额:
    $ 24.16万
  • 项目类别:
MMP-9 AS A PROINFLAMMATORY REGULATOR IN ATHEROGENESIS
MMP-9 作为动脉粥样硬化形成中的促炎调节剂
  • 批准号:
    7923973
  • 财政年份:
    2005
  • 资助金额:
    $ 24.16万
  • 项目类别:
MMP-9 AS A PROINFLAMMATORY REGULATOR IN ATHEROGENESIS
MMP-9 作为动脉粥样硬化形成中的促炎调节剂
  • 批准号:
    7729741
  • 财政年份:
    2005
  • 资助金额:
    $ 24.16万
  • 项目类别:
MMP-9 AS A PROINFLAMMATORY REGULATOR IN ATHEROGENESIS
MMP-9 作为动脉粥样硬化形成中的促炎调节剂
  • 批准号:
    7074635
  • 财政年份:
    2005
  • 资助金额:
    $ 24.16万
  • 项目类别:
MMP-9 AS A PROINFLAMMATORY REGULATOR IN ATHEROGENESIS
MMP-9 作为动脉粥样硬化形成中的促炎调节剂
  • 批准号:
    7236746
  • 财政年份:
    2005
  • 资助金额:
    $ 24.16万
  • 项目类别:

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