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Regulation of Vascular Inflammatory Signaling by the Deubiquitinase USP20

Regulation of Vascular Inflammatory Signaling by the Deubiquitinase USP20
去泛素酶 USP20 对血管炎症信号的调节
批准号:
10112295
负责人:
NEIL J. FREEDMAN
金额:
$53.46万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-03-15 至 2023-02-28

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英文摘要
PROJECT SUMMARY We recently demonstrated that ubiquitin-specific protease-20 (USP20) is scaffolded by the adaptor protein known as β-arrestin2 (βarr2), and that USP20 desensitizes ubiquitin-dependent signaling from Toll-like receptor-4 (TLR4) to NFκB activation by deubiquitinating TRAF6 and βarr2. Using transgenic mice expressing dominant-negative USP20 in smooth muscle cells, we found that USP20 reduces neointimal hyperplasia after arterial injury and that USP20 activity in SMCs reduces atherosclerosis in Ldlr-/- mice. To establish anti-atherogenic effects of systemically expressed USP20, and to elucidate further molecular mechanisms by which USP20 protects against atherosclerosis, this project will test the hypothesis that USP20 attenuates atherosclerosis by deubiquitinating several substrate proteins that were previously unassociated with USP20 but that are important in signaling pathways that activate NFκB: βarr1, TRAF6, TRAF2, and RIPK1. Furthermore, because USP20 employs βarr2 as a scaffold to facilitate association with distinct proteins, and because βarr1 reduces vascular inflammation, this project will test whether USP20’s anti-atherogenic activity involves βarr1-mediated scaffolding. To these ends, this project will study systemic effects of USP20 on atherosclerosis by comparing Usp20-/- /Ldlr-/- versus Ldlr-/- mice, on a background of βarr1+/+ or βarr1-/+. To determine the effects of endothelial USP20 on atherosclerosis, this project will compare atherosclerosis among VECad-Cre- ERT2/Usp20flox/flox/Ldlr-/- vs. Usp20flox/flox/Ldlr-/- mice treated ± tamoxifen; furthermore, we will investigate cytokine secretion, and dynamic ubiquitination of signaling proteins in primary aortic endothelial cells that are WT, Usp20-/-, Usp20-/-/βarr1-/+, or βarr1-/-. To determine what kinase in endothelial cells phosphorylates USP20 on Ser333 (and thereby abrogates USP20 deubiquitinase activity), this project will test IRAK1, PAK1, and ROCK1 with several loss-of function approaches, including a USP20 minigene, in primary endothelial cells. These studies collectively may identify USP20 phosphorylation as novel therapeutic target for atherosclerosis.
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Mechanisms by which Small Nucleolar RNAs Exacerbate Atherosclerosis
  • 批准号:
    10502380
  • 项目类别:
  • 资助金额:
    $58.7万
  • 财政年份:
    2022
  • 负责人:
    NEIL J. FREEDMAN
  • 依托单位:
Mechanisms by which Small Nucleolar RNAs Exacerbate Atherosclerosis
  • 批准号:
    10670399
  • 项目类别:
  • 资助金额:
    $58.7万
  • 财政年份:
    2022
  • 负责人:
    NEIL J. FREEDMAN
  • 依托单位:
Anti-Atherogenic Mechanisms of Drebrin
  • 批准号:
    10318175
  • 项目类别:
  • 资助金额:
    $52.33万
  • 财政年份:
    2019
  • 负责人:
    NEIL J. FREEDMAN
  • 依托单位:
Anti-Atherogenic Mechanisms of Drebrin
  • 批准号:
    10532356
  • 项目类别:
  • 资助金额:
    $52.33万
  • 财政年份:
    2019
  • 负责人:
    NEIL J. FREEDMAN
  • 依托单位:
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