Regulation of IL-1β bioactivity by Cysteine S-glutathionylation
半胱氨酸 S-谷胱甘肽化调节 IL-1β 生物活性
基本信息
- 批准号:10620756
- 负责人:
- 金额:$ 16.53万
- 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:2019-06-12 至 2024-04-14
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAffectBiochemicalBone MarrowBone Marrow CellsBone Marrow PurgingCellsCysteineDose LimitingEnzymesEventExtracellular SpaceGenerationsGenetic TranscriptionGlutathioneGlutathione DisulfideGrx1 proteinHematopoietic SystemHost DefenseHydrogen PeroxideIn VitroInfectionInflammasomeInflammationInterleukin-1 betaInvadedMass Spectrum AnalysisMeasuresMediatingModelingModificationMusPathway interactionsPatientsPattern recognition receptorPhysiologicalPlayPost-Translational Protein ProcessingProductionProtein SProteinsRadiation ToxicityRadiation therapyReactive Oxygen SpeciesRecoveryRegulationReportingResearchRoleSerumStressSulfinic AcidsSulfonic AcidsSystemTestingTherapeutic InterventionThiol Disulfide OxidoreductaseTissuesTranslational ResearchUp-Regulationcell typeclinical applicationclinically relevantcysteine sulfinic acidcytokinedisulfide bondexperimental studyextracellulargamma irradiationglutaredoxinimprovedin vivointravenous injectionirradiationmutantnew therapeutic targetnovelnovel therapeutic interventionoxidationpathogenpreventprotective effectprotein Bthioltransferase
项目摘要
Project Summary
IL-1β is a major player in host defense against invading pathogens. Conversely, excessive IL-1β production
and/or activation can be detrimental to the system, resulting in unwanted and exaggerated tissue inflammation.
Hence, the bioactivity of IL-1β needs to be well controlled. Mechanisms of IL-1β regulation have traditionally
focused on pattern recognition receptor-induced gene transcription and inflammasome-mediated cleavage of
pro-IL-1β. The complete IL-1β cytokine regulatory repertoire is still largely unknown. The objective of the
proposed research is to identify and characterize biochemical events that modulate the bioactivity of mature IL-
1β after its release from the cells. We recently found that cysteine S-glutathionylation of the highly conserved
Cys-188 residue in IL-1β positively regulates IL-1β bioactivity by preventing its irreversible reactive oxygen
species (ROS)-elicited oxidation and deactivation. Protein glutathionylation is dynamic and reversible. We
further demonstrated that Glutaredoxin 1 (Grx1), an enzyme that catalyzes deglutathionylation, is present and
active in the extracellular space in serum and BM, and physiologically regulates IL-1β glutathionylation.
Together, these results lead us to hypothesize that ROS-induced cysteine S-glutathionylation and its
modulation by Grx1 are key regulatory mechanisms controlling IL-1β activity under pathophysiological
conditions. In current study, we will test this hypothesis in a clinically relevant model in which IL-1β activity is
both essential and sufficient for efficient recovery of the hematopoietic system after irradiation. First, we will
determine the role of cysteine S-glutathionylation in regulating the bioactivity of endogenously produced IL-1β
during bone marrow (BM) recovery after irradiation (Aim I). In addition, we will elucidate the function of Grx1 in
regulating S-glutathionylation of endogenously produced IL-1β in BM recovery in irradiated mice. We will also
identify the cell types that produce Grx1 in the BM (Aim II). Finally, we will try to accelerate BM recovery after
irradiation by targeting IL-1β S-glutathionylation. We will first examine whether glutathione intravenous injection
(GSH IV) therapy can elevate IL-1β bioactivity and accelerate the recovery of the hematopoietic system in
irradiated mice. In addition, we will investigate whether IL-1β 188C/S, a mutant form of IL-1β that can not be
oxidized and deactivated, is more potent in eliciting BM protective effect in irradiated mice compared to WT IL-
1β (Aim III). Together, experiments proposed in these three specific aims will provide a better understanding of
the role of ROS-induced cysteine S-glutathionylation in controlling IL-1β activity in vivo in clinically relevant
settings. Toward the translational research paradigm, results from this study will assist us to identify novel
therapeutic targets (e.g. ROS, Grx1, and related pathways) for accelerating BM recovery in patients receiving
radiotherapy.
项目总结
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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Hongbo R Luo其他文献
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{{ truncateString('Hongbo R Luo', 18)}}的其他基金
Novel Strategies to Improve Blood Transfusion Practice
改善输血实践的新策略
- 批准号:
10494380 - 财政年份:2022
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$ 16.53万 - 项目类别:
Novel Strategies to Improve Blood Transfusion Practice
改善输血实践的新策略
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10682582 - 财政年份:2022
- 资助金额:
$ 16.53万 - 项目类别:
Improving granulocyte transfusion in neutropenia-related infections
改善中性粒细胞减少相关感染的粒细胞输注
- 批准号:
10494384 - 财政年份:2022
- 资助金额:
$ 16.53万 - 项目类别:
Improving granulocyte transfusion in neutropenia-related infections
改善中性粒细胞减少相关感染的粒细胞输注
- 批准号:
10682602 - 财政年份:2022
- 资助金额:
$ 16.53万 - 项目类别:
Regulation of neutrophil death by GSDMD in Candida albicans infection
GSDMD 对白色念珠菌感染中性粒细胞死亡的调节
- 批准号:
10229487 - 财政年份:2019
- 资助金额:
$ 16.53万 - 项目类别:
Regulation of neutrophil death by GSDMD in Candida albicans infection
GSDMD 对白色念珠菌感染中性粒细胞死亡的调节
- 批准号:
10687091 - 财政年份:2019
- 资助金额:
$ 16.53万 - 项目类别:
Regulation of neutrophil death by GSDMD in Candida albicans infection
GSDMD 对白色念珠菌感染中性粒细胞死亡的调节
- 批准号:
9894354 - 财政年份:2019
- 资助金额:
$ 16.53万 - 项目类别:
Regulation of IL-1β bioactivity by Cysteine S-glutathionylation
半胱氨酸 S-谷胱甘肽化调节 IL-1β 生物活性
- 批准号:
10405596 - 财政年份:2019
- 资助金额:
$ 16.53万 - 项目类别:
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