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.
项目总结
我们最近证明泛素特异性蛋白水解酶-20(USP20)是以接头为骨架的
被称为β-arrestin2(βarr2)的蛋白质,并且USP20使泛素依赖的信号从
Toll样受体4通过去泛素化TRAF6和κArr2激活核因子βB。使用转基因技术
在血管细胞中表达显性阴性USP20的小鼠,我们发现USP20减少了
动脉损伤后新生内膜增生及SMC中USP20活性降低动脉粥样硬化
LDLR-/-小鼠。建立系统表达的USP20的抗动脉粥样硬化作用,并阐明
该项目将测试USP20预防动脉粥样硬化的进一步分子机制
USP20通过去泛素化几种底物蛋白减轻动脉粥样硬化的假说
它们以前与USP20无关,但在激活的信号通路中很重要
核因子κB:βARR1、TRAF6、TRAF2和RIPK1。此外,由于USP20使用βARR2作为脚手架
为了促进与不同蛋白质的联系,并且因为βarr1减少血管炎症,这
该项目将测试USP20的S抗动脉粥样硬化活性是否涉及βArr1介导的支架。至
最后,本项目将通过比较USP20-/-来研究USP20在动脉粥样硬化中的系统作用
/Ldlr-/-对Ldlr-/-小鼠,背景为βarr1+/+或βarr1-/+。确定血管内皮细胞的作用
USP20关于动脉粥样硬化,本项目将比较VECad-CRE-
ERT2/Usp20Flox/Flox/Ldlr-/-vs.Usp20Flox/Flox/Ldlr-/-治疗的小鼠±他莫昔芬;此外,我们将研究
原代主动脉内皮细胞细胞因子分泌与信号蛋白的动态泛素化
它们是WT、USP20-/-、USP20-/-/βARR1-/+或βARR1-/-。要确定内皮细胞中的哪种激酶
使Ser333上的USP20磷酸化(从而取消USP20去泛素酶活性),该项目
将使用几种功能丧失方法测试IRAK1、PAK1和ROCK1,包括USP20
微基因,在原代内皮细胞中。这些研究可能共同确定USP20的磷酸化
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:
10502380 - 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:
10670399 - 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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