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

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 骨髓中的造血干细胞(HSC)增殖并将其分化转向髓系。 人们对理解触发这种紧急造血的信号产生了极大的兴趣 程序.然而,终止HSC的这种反应并恢复组织的机制, 体内平衡仍然未知。蛋白酶体抑制剂硼替佐米和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,确定新的E3连接酶如何在骨髓中发挥作用,并研究它们在骨髓中的作用。 在正常和紧急造血中的特定作用可以导致新的治疗干预。我们有 证明了E3泛素连接酶Spop抑制HSC的炎性活化。在没有 在Spop中,全身性炎症以未解决的方式进行,并且HSC中的持续反应 导致致死性表型,使人联想到高度炎症综合征。我们的蛋白质组学/生物化学 研究表明,Spop通过靶向信号转导子Myd 88来限制炎症, 蛋白酶体依赖性降解。Myd 88的积累与炎症刺激一起导致 Myddosome的形成,PK 4激酶的过度磷酸化和一些 转录因子途径(NF-kB,Jun,Pu.1,Cebpb)。该提案定义:(a)转录和 在急性造血的开始和终止过程中施加的染色质景观变化 骨髓HSC和祖细胞,(B)mydosome组装、信号传导和终止的作用 在紧急造血和基因调控和(c)mydosome装配的结构细节, 终止这项拨款提案的结果将揭示HSC的内在机制, 在紧急造血后重建体内平衡

项目成果

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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:
    $ 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:
Mechanisms of enhancer regulation in leukemia
白血病增强子调控机制
  • 批准号:
    10545714
  • 财政年份:
    2019
  • 资助金额:
    $ 65.32万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    10434092
  • 财政年份:
    2019
  • 资助金额:
    $ 65.32万
  • 项目类别:
Mechanisms of enhancer regulation in leukemia
白血病增强子调控机制
  • 批准号:
    10321638
  • 财政年份:
    2019
  • 资助金额:
    $ 65.32万
  • 项目类别:

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  • 批准号:
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  • 财政年份:
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