Regulation of the IL-33 receptor, ST2L, by Protein Stability in Septic Injury
脓毒性损伤中蛋白质稳定性对 IL-33 受体 ST2L 的调节
基本信息
- 批准号:8851660
- 负责人:
- 金额:$ 37.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-06-01 至 2016-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Lung InjuryAnti-Inflammatory AgentsAnti-inflammatoryApoptosisAttenuatedBehaviorBindingChronicComplexCytokine ReceptorsDataDevelopmentEndotoxinsExhibitsF Box DomainF-Box ProteinsFamilyGenesGlycogen Synthase KinasesHealthImmunologyInflammationInflammatoryInjuryKnockout MiceLigandsLigationLysosomesMediatingMedicineModelingMolecularMolecular ProfilingMusNatureOrganOrphanPathway interactionsPatientsPhosphorylationProcessProteinsPublishingPulmonary InflammationRegulationRespiratory FailureSchemeSepsisSeptic ShockSeveritiesSignal TransductionSurfaceSystemTestingTherapeuticTherapeutic InterventionUbiquitinationWorkbasecell injurycytokinedesigninhibitor/antagonistlung injurymulticatalytic endopeptidase complexneutralizing antibodynovelnovel strategiesreceptorsepticsmall moleculeubiquitin-protein ligase
项目摘要
DESCRIPTION (provided by applicant): IL-33, acting via its receptor, ST2L, is a highly potent cytokine implicated in septic injury. The IL-33/ST2L axis appears indispensable in inflammatory signaling as blockade of the ST2L receptor significantly attenuates systemic inflammation. Thus, maneuvers designed to selectively modulate availability of ST2L might lessen the severity of sepsis. However, to date, very little is known regarding the molecular regulation of ST2L expression. In the process of studying bacterial sepsis, we discovered that a new orphan protein, FBXL19 (F-box protein 19, SCFFBXL19), specifically targets phosphorylated ST2L for its ubiquitination and degradation. Our published and preliminary works also shows that ST2L is phosphorylated by glycogen synthase kinase (GSK3¿), and that activation of the IL-33/ST2L axis induces cleavage of PARP and PKC¿ thereby promoting apoptosis. Further, FBXL19 mediated disposal of ST2L attenuates IL-33/ST2L-induced pro-inflammatory signaling, apoptosis, and lessens the severity of inflammatory organ injury in septic murine models. These data led to our novel hypothesis that GSK3¿-driven phosphorylation of ST2L serves as a molecular signature for F-box protein mediated ubiquitination and degradation of ST2L in sepsis-associated injury. We will test this hypothesis by executing two specific Aims: (1) To investigate the mechanisms by which GSK3¿ promotes ST2L degradation and regulates IL-33/ST2L signaling, and (2) To investigate the mechanisms by which FBXL19 and its ligand promotes ST2L ubiquitination and degradation thereby attenuating septic lung injury. These studies will lay the groundwork for a significant mechanistic advance with regard to the molecular regulation of a relatively new receptor (ST2L) involved in sepsis. Results from these studies are intended to serve as the basis for strategies directed at the development of novel small molecule inhibitors of the IL-33/ST2L pathway to lessen the severity of sepsis-induced organ injury.
描述(由申请人提供):IL-33通过其受体ST 2L起作用,是一种与脓毒性损伤有关的高效细胞因子。IL-33/ST 2L轴似乎在炎症信号传导中不可或缺,因为ST 2L受体的阻断显著减弱全身性炎症。因此,旨在选择性调节ST 2L可用性的策略可能会减轻脓毒症的严重程度。然而,迄今为止,很少有人知道关于ST 2L表达的分子调控。在研究细菌性脓毒症的过程中,我们发现一种新的孤儿蛋白FBXL 19(F-box protein 19,SCFFBXL 19)特异性靶向磷酸化的ST 2L,使其泛素化和降解。我们已发表的和初步的工作也表明,ST 2L被糖原合成酶激酶(GSK 3 <$)磷酸化,IL-33/ST 2L轴的激活诱导PARP和PKC <$的裂解,从而促进细胞凋亡。此外,FBXL 19介导的ST 2L处置减弱IL-33/ST 2L诱导的促炎信号传导、细胞凋亡,并减轻脓毒症鼠模型中炎性器官损伤的严重程度。这些数据导致我们的新假设,即GSK 3-驱动的ST 2L磷酸化是脓毒症相关损伤中F-box蛋白介导的ST 2L泛素化和降解的分子标志。我们将通过执行两个特定的目的来验证这一假设:(1)研究GSK 3促进ST 2L降解和调节IL-33/ST 2L信号传导的机制,以及(2)研究FBXL 19及其配体促进ST 2L泛素化和降解从而减轻脓毒性肺损伤的机制。这些研究将为脓毒症中一种相对较新的受体(ST 2L)的分子调控奠定基础。这些研究的结果旨在作为开发IL-33/ST 2L途径的新型小分子抑制剂以减轻脓毒症诱导的器官损伤严重程度的策略的基础。
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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Yutong Zhao其他文献
Yutong Zhao的其他文献
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ISGylation regulates lung endothelial inflammation
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ISGylation regulates lung endothelial inflammation
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Molecular regulation of anti-inflammatory cytokine receptor in sepsis
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- 批准号:
9912821 - 财政年份:2018
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Regulation of proteolysis by deubiquiting enzyme in lung inflammatory disease
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9912813 - 财政年份:2018
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Regulation of proteolysis by deubiquiting enzyme in lung inflammatory disease
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9237362 - 财政年份:2017
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$ 37.39万 - 项目类别:
Regulation of the IL-33 receptor, ST2L, by Protein Stability in Septic Injury
脓毒性损伤中蛋白质稳定性对 IL-33 受体 ST2L 的调节
- 批准号:
8666032 - 财政年份:2013
- 资助金额:
$ 37.39万 - 项目类别:
Regulation of the IL-33 receptor, ST2L, by Protein Stability in Septic Injury
脓毒性损伤中蛋白质稳定性对 IL-33 受体 ST2L 的调节
- 批准号:
9067468 - 财政年份:2013
- 资助金额:
$ 37.39万 - 项目类别:
Regulation of the IL-33 receptor, ST2L, by Protein Stability in Septic Injury
脓毒性损伤中蛋白质稳定性对 IL-33 受体 ST2L 的调节
- 批准号:
8499556 - 财政年份:2013
- 资助金额:
$ 37.39万 - 项目类别:
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