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:10279596
- 负责人:
- 金额:$ 65.32万
- 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 CompartmentationCellsChemicalsChromatinClinicalComplexCytokine ReceptorsDataDiagnosticEmergency SituationGene ExpressionGene Expression RegulationGenetic TranscriptionGluesHematological DiseaseHematopoiesisHematopoieticHematopoietic SystemHematopoietic stem cellsHomeostasisIRAK2 geneImmune responseImmune systemIn VitroInflammationInflammatoryInflammatory ResponseInjuryInterventionKnowledgeLeadLigaseLinkMalignant NeoplasmsMapsMediatingModelingMolecularMolecular ConformationMultiprotein ComplexesMutant Strains MiceMyD88 proteinMyelogenousNF-kappa BNamesNeutrophiliaOrganismOutputPathologyPathway interactionsPhenotypePhosphotransferasesPoisonPost-Translational RegulationProcessProliferatingProteasome InhibitorProteomicsRegulationResearchResolutionRoleSignal PathwaySignal TransductionStimulusStructureSyndromeSystemSystemic infectionTherapeuticTherapeutic InterventionTissuesToll-like receptorsTranscriptional RegulationTransducersUbiquitinUbiquitinationViralbasecell injurychronic inflammatory diseaseconditional knockoutepigenomicshealinghematopoietic tissuein vivointerestirradiationmulticatalytic endopeptidase complexmutantnovelnovel therapeutic interventionpathogenpersonalized therapeuticprogramsprotein degradationrecruitresponserestorationrole 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.
项目摘要
对全身感染和组织损伤的反应需要造血干细胞的快速适应。
骨髓中的干细胞(HSCs),增殖并将其分化为髓系。
人们对了解触发这种紧急造血的信号产生了浓厚的兴趣
程序。然而,终止造血干细胞这种反应并恢复组织的机制
动态平衡仍然未知。蛋白酶体抑制剂Bortezomib和E3泛素的临床成功
用于治疗血液病的连接酶胶使泛素途径成为真正的靶点
癌症治疗学。因此,定义新的E3连接酶在骨髓中的功能并研究它们的
在正常和紧急造血中的特殊作用可以导致新的治疗干预措施。我们有
证明E3泛素连接酶SPOP抑制HSCs的炎症激活。在缺席时
在SPOP中,全身性炎症以未解决的方式进行,HSCs的持续反应
结果导致一种致命的表型,使人联想到高炎症综合征。我们的蛋白质组学/生物化学
研究表明,SPOP通过靶向MyD88信号转导通路来抑制炎症
依赖蛋白酶体的降解。MyD88积聚与炎症刺激相结合导致
对肌小体的形成,IRAK4激酶的过度磷酸化和一些
转录因子途径(核因子-kB、Jun、PU.1、CEBPB)。该提案界定:(A)抄本和
急诊造血启动和终止过程中染色质景观的变化
骨髓HSC和祖细胞,(B)肌小体组装、信号传递和终止的作用
在紧急造血和基因调控中的作用以及(C)myddosome组装和
终止。这项赠款提案的发现将揭示HSC的内在机制
在紧急造血后重建内环境平衡。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Iannis Aifantis其他文献
Iannis Aifantis的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
$ 65.32万 - 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:
$ 65.32万 - 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:
$ 65.32万 - 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:
$ 65.32万 - 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:
$ 65.32万 - 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:
10634676 - 财政年份:2021
- 资助金额:
$ 65.32万 - 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:
$ 65.32万 - 项目类别:
相似海外基金
Elucidating the biophysics of pre-fibrillar, toxic tau oligomers: from amino acid motifs to neuronal dysfunction
阐明前原纤维有毒 tau 寡聚体的生物物理学:从氨基酸基序到神经元功能障碍
- 批准号:
10461322 - 财政年份:2021
- 资助金额:
$ 65.32万 - 项目类别:
Elucidating the biophysics of pre-fibrillar, toxic tau oligomers: from amino acid motifs to neuronal dysfunction
阐明前原纤维有毒 tau 寡聚体的生物物理学:从氨基酸基序到神经元功能障碍
- 批准号:
10489810 - 财政年份:2021
- 资助金额:
$ 65.32万 - 项目类别:
Detection of amino acid motifs on the agretopes of antigens highly bound to MHC molecules
检测与 MHC 分子高度结合的抗原聚集位上的氨基酸基序
- 批准号:
03670243 - 财政年份:1991
- 资助金额:
$ 65.32万 - 项目类别:
Grant-in-Aid for General Scientific Research (C)