Regulation of emergency hematopoiesis by the ubiquitin-proteasome system
泛素-蛋白酶体系统对紧急造血的调节
基本信息
- 批准号:10634676
- 负责人:
- 金额:$ 62.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAmino Acid MotifsAnimal ModelApplications GrantsAreaAutomobile DrivingBindingBiochemicalBone MarrowBortezomibCell CommunicationCell CompartmentationCellsChemicalsChromatinClinicalComplexCytokine ReceptorsDataDiagnosticEmergency SituationGene ExpressionGene Expression RegulationGenetic TranscriptionGluesHematological DiseaseHematopoiesisHematopoieticHematopoietic SystemHematopoietic stem cellsHomeostasisIL1R1 geneIRAK2 geneImmune responseImmune systemIn VitroInflammationInflammatoryInflammatory ResponseInjuryInterventionKnowledgeLigaseLinkMalignant NeoplasmsMapsMediatingModelingMolecularMolecular ConformationMultiprotein ComplexesMutant Strains MiceMyD88 proteinMyelogenousNF-kappa BNamesNeutrophiliaOrganismOutputPathologyPathway interactionsPhenotypePhosphotransferasesPoisonPost-Translational RegulationProcessProliferatingProteasome InhibitorProteomicsRegulationResearchResolutionRoleSignal PathwaySignal TransductionStimulusStructureSyndromeSystemSystemic infectionTherapeuticTherapeutic InterventionTissuesToll-like receptorsTranscriptional RegulationTransducersUbiquitinUbiquitinationViralcell injurychronic inflammatory diseaseconditional knockoutepigenomicshealinghematopoietic tissuein vivointerestirradiationmulticatalytic endopeptidase complexmutantnovelnovel therapeutic interventionpathogenpersonalized therapeuticprogramsprotein degradationrecruitresponserestorationrestraintrole modelstem cellsstoichiometrysuccesssystemic inflammatory responsetissue injurytranscription factortranscriptomicsubiquitin-protein ligase
项目摘要
Project Summary
The response to systemic infection and tissue injury requires the rapid adaptation of hematopoietic stem cells
(HSCs) in the bone marrow, which proliferate and divert their differentiation towards the myeloid lineage.
Significant interest has emerged in understanding the signals that trigger this emergency hematopoietic
program. However, the mechanisms that terminate this response of the HSCs and restore tissue
homeostasis remain unknown. The clinical success of proteasome inhibitors, bortezomib, and E3 ubiquitin
ligase glues for the treatment of hematologic diseases has made the Ubiquitin pathway a bona fide target for
cancer therapeutics. Thus, defining how novel E3 ligases function in the bone marrow and investigating their
specific roles in normal and emergency hematopoiesis can lead to novel therapeutic interventions. We have
demonstrated that the E3 ubiquitin ligase Spop restrains the inflammatory activation of HSCs. In the absence
of Spop, systemic inflammation proceeds in an unresolved manner and the sustained response in the HSCs
results in a lethal phenotype reminiscent of hyper-inflammatory syndrome. Our proteomic/biochemical
studies demonstrated that Spop restricts inflammation by targeting the signal transducer Myd88 for
proteasome-dependent degradation. Myd88 accumulation in conjunction with an inflammatory stimulus leads
to Myddosome formation, the hyper-phosphorylation of the Irak4 kinase and activation of a number of
transcription factor pathways (NF-kB, Jun, Pu.1, Cebpb). This proposal defines: (a) the transcriptional and
chromatin landscape changes imposed during initiation and termination of emergency hematopoiesis in the
bone marrow HSC and progenitor cells, (b) the role of the myddosome assembly, signaling and termination
in emergency hematopoiesis and gene regulation and (c) the structural details of myddosome assembly and
termination. The findings of this grant proposal will uncover HSC-intrinsic mechanisms essential for
reestablishing homeostasis following emergency hematopoiesis.
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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Iannis Aifantis其他文献
Iannis Aifantis的其他文献
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{{ truncateString('Iannis Aifantis', 18)}}的其他基金
The role of inflammation in the regulation of immune response in acute myeloid leukemia
炎症在急性髓系白血病免疫反应调节中的作用
- 批准号:
10729281 - 财政年份:2023
- 资助金额:
$ 62.79万 - 项目类别:
Dissecting innate immune signaling in pre-leukemia evolution
剖析白血病前期进化中的先天免疫信号
- 批准号:
10584536 - 财政年份:2022
- 资助金额:
$ 62.79万 - 项目类别:
Dissecting innate immune signaling in pre-leukemia evolution
剖析白血病前期进化中的先天免疫信号
- 批准号:
10462192 - 财政年份:2022
- 资助金额:
$ 62.79万 - 项目类别:
mRNA stability and its impact on hematopoiesis and acute leukemia
mRNA稳定性及其对造血和急性白血病的影响
- 批准号:
10339742 - 财政年份:2022
- 资助金额:
$ 62.79万 - 项目类别:
mRNA stability and its impact on hematopoiesis and acute leukemia
mRNA稳定性及其对造血和急性白血病的影响
- 批准号:
10543125 - 财政年份:2022
- 资助金额:
$ 62.79万 - 项目类别:
Regulation of emergency hematopoiesis by the ubiquitin-proteasome system
泛素-蛋白酶体系统对紧急造血的调节
- 批准号:
10279596 - 财政年份:2021
- 资助金额:
$ 62.79万 - 项目类别:
Project 3: Oncogenic triggers and their influence on 3D chromosomal architecture
项目 3:致癌触发因素及其对 3D 染色体结构的影响
- 批准号:
10652283 - 财政年份:2019
- 资助金额:
$ 62.79万 - 项目类别:
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