Regulation of Vascular Inflammatory Signaling by the Deubiquitinase USP20
去泛素酶 USP20 对血管炎症信号的调节
基本信息
- 批准号:9893026
- 负责人:
- 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
- 起止时间:2019-03-15 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:Adaptor Signaling ProteinAdenovirusesAmino AcidsAnti-Inflammatory AgentsAntiatherogenicArrestinsArterial InjuryAtherosclerosisAttenuatedBindingBiological AssayBlood VesselsCCL2 geneCRISPR/Cas technologyCause of DeathCell Adhesion MoleculesChronicCytokine ReceptorsDeubiquitinationDominant-Negative MutationEndothelial CellsEndotheliumFamilyGoalsHumanHyperplasiaI Kappa B-AlphaIRAK1 geneIn VitroIndustrializationInflammationInflammatoryInterleukin 4 ReceptorInterleukin-1 ReceptorsLOX geneLinkLipopolysaccharidesMediatingMolecularMusMyocardial InfarctionPartner in relationshipPhosphorylationPhosphotransferasesPolyubiquitinationPost-Translational Protein ProcessingProtein KinaseProteinsRIPK1 geneROCK1 geneRegulationRoleSignal PathwaySignal TransductionSignaling ProteinSmooth Muscle MyocytesStrokeTLR2 geneTLR4 geneTNF geneTNFRSF1A geneTRAF2 geneTRAF6 geneTamoxifenTestingTransgenic MiceTransgenic OrganismsTumor Necrosis Factor ReceptorUbiquitinUbiquitinationatherogenesiscellular transductioncongeniccytokinedesensitizationin vivointerleukin-1 receptor-associated kinaseloss of functionlysophosphatidic acidmacrophagemutantnew therapeutic targetnovelprotein Bresponsescaffoldtranscription factorubiquitin-protein ligaseubiquitin-specific proteasevascular inflammationwestern diet
项目摘要
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.
项目概要
我们最近证明泛素特异性蛋白酶 20 (USP20) 由接头支架构成
称为 β-arrestin2 (βarr2) 的蛋白质,USP20 使泛素依赖性信号通路脱敏
Toll 样受体 4 (TLR4) 通过去泛素化 TRAF6 和 βarr2 来激活 NFκB。使用转基因
在平滑肌细胞中表达显性失活 USP20 的小鼠中,我们发现 USP20 降低
动脉损伤后新生内膜增生以及 SMC 中的 USP20 活性可减少动脉粥样硬化
Ldlr-/- 小鼠。确定系统表达的 USP20 的抗动脉粥样硬化作用,并阐明
USP20 预防动脉粥样硬化的进一步分子机制,该项目将测试
USP20 通过使几种底物蛋白去泛素化来减轻动脉粥样硬化的假设
以前与 USP20 无关,但在激活的信号通路中很重要
NFκB:βarr1、TRAF6、TRAF2 和 RIPK1。此外,由于USP20采用βarr2作为支架
为了促进与不同蛋白质的结合,并且由于 βarr1 减少血管炎症,这
该项目将测试 USP20 的抗动脉粥样硬化活性是否涉及 βarr1 介导的支架。到
为此,本项目将通过比较 Usp20-/- 来研究 USP20 对动脉粥样硬化的全身影响
/Ldlr-/- 与 Ldlr-/- 小鼠相比,以 βarr1+/+ 或 βarr1-/+ 为背景。确定内皮细胞的影响
USP20 关于动脉粥样硬化,该项目将比较 VECad-Cre- 之间的动脉粥样硬化
ERT2/Usp20flox/flox/Ldlr-/- 与 Usp20flox/flox/Ldlr-/- 治疗小鼠±他莫昔芬;此外,我们将调查
原代主动脉内皮细胞中细胞因子的分泌和信号蛋白的动态泛素化
分别是 WT、Usp20-/-、Usp20-/-/βarr1-/+ 或 βarr1-/-。确定内皮细胞中的激酶
在 Ser333 上磷酸化 USP20(从而消除 USP20 去泛素酶活性),该项目
将使用多种功能丧失方法(包括 USP20)测试 IRAK1、PAK1 和 ROCK1
原代内皮细胞中的小基因。这些研究共同可能确定 USP20 磷酸化
作为动脉粥样硬化的新治疗靶点。
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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NEIL J. FREEDMAN其他文献
NEIL J. FREEDMAN的其他文献
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{{ truncateString('NEIL J. FREEDMAN', 18)}}的其他基金
Mechanisms by which Small Nucleolar RNAs Exacerbate Atherosclerosis
小核仁 RNA 加剧动脉粥样硬化的机制
- 批准号:
10670399 - 财政年份:2022
- 资助金额:
$ 53.46万 - 项目类别:
Mechanisms by which Small Nucleolar RNAs Exacerbate Atherosclerosis
小核仁 RNA 加剧动脉粥样硬化的机制
- 批准号:
10502380 - 财政年份:2022
- 资助金额:
$ 53.46万 - 项目类别:
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:
9765984 - 财政年份:2019
- 资助金额:
$ 53.46万 - 项目类别:
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:
10349573 - 财政年份:2019
- 资助金额:
$ 53.46万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 53.46万 - 项目类别:
Regulation of B-arrestin2's pro-atherogenic activity by the deubiquitinase USP20
去泛素酶 USP20 对 B-arrestin2 促动脉粥样硬化活性的调节
- 批准号:
8797106 - 财政年份:2014
- 资助金额:
$ 53.46万 - 项目类别:
Regulation of B-arrestin2's pro-atherogenic activity by the deubiquitinase USP20
去泛素酶 USP20 对 B-arrestin2 促动脉粥样硬化活性的调节
- 批准号:
8639259 - 财政年份:2014
- 资助金额:
$ 53.46万 - 项目类别:
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