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：
Iannis Aifantis
金额：
$ 62.79万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
https://reporter.nih.gov/project-details/10634676
关键词：
Acute Amino Acid Motifs Animal Model Applications Grants Area Automobile Driving Binding Biochemical Bone Marrow Bortezomib Cell Communication Cell Compartmentation Cells Chemicals Chromatin Clinical Complex Cytokine Receptors Data Diagnostic Emergency Situation Gene Expression Gene Expression Regulation Genetic Transcription Glues Hematological Disease Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Homeostasis IL1R1 gene IRAK2 gene Immune response Immune system In Vitro Inflammation Inflammatory Inflammatory Response Injury Intervention Knowledge Ligase Link Malignant Neoplasms Maps Mediating Modeling Molecular Molecular Conformation Multiprotein Complexes Mutant Strains Mice MyD88 protein Myelogenous NF-kappa B Names Neutrophilia Organism Output Pathology Pathway interactions Phenotype Phosphotransferases Poison Post-Translational Regulation Process Proliferating Proteasome Inhibitor Proteomics Regulation Research Resolution Role Signal Pathway Signal Transduction Stimulus Structure Syndrome System Systemic infection Therapeutic Therapeutic Intervention Tissues Toll-like receptors Transcriptional Regulation Transducers Ubiquitin Ubiquitination Viral cell injury chronic inflammatory disease conditional knockout epigenomics healing hematopoietic tissue in vivo interest irradiation multicatalytic endopeptidase complex mutant novel novel therapeutic intervention pathogen personalized therapeutic programs protein degradation recruit response restoration restraint role model stem cells stoichiometry success systemic inflammatory response tissue injury transcription factor transcriptomics ubiquitin-protein ligase

Acute Amino Acid Motifs Animal Model Applications Grants Area Automobile Driving Binding Biochemical Bone Marrow Bortezomib Cell Communication Cell Compartmentation Cells Chemicals Chromatin Clinical Complex Cytokine Receptors Data Diagnostic Emergency Situation Gene Expression Gene Expression Regulation Genetic Transcription Glues Hematological Disease Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Homeostasis IL1R1 gene IRAK2 gene Immune response Immune system In Vitro Inflammation Inflammatory Inflammatory Response Injury Intervention Knowledge Ligase Link Malignant Neoplasms Maps Mediating Modeling Molecular Molecular Conformation Multiprotein Complexes Mutant Strains Mice MyD88 protein Myelogenous NF-kappa B Names Neutrophilia Organism Output Pathology Pathway interactions Phenotype Phosphotransferases Poison Post-Translational Regulation Process Proliferating Proteasome Inhibitor Proteomics Regulation Research Resolution Role Signal Pathway Signal Transduction Stimulus Structure Syndrome System Systemic infection Therapeutic Therapeutic Intervention Tissues Toll-like receptors Transcriptional Regulation Transducers Ubiquitin Ubiquitination Viral cell injury chronic inflammatory disease conditional knockout epigenomics healing hematopoietic tissue in vivo interest irradiation multicatalytic endopeptidase complex mutant novel novel therapeutic intervention pathogen personalized therapeutic programs protein degradation recruit response restoration restraint role model stem cells stoichiometry success systemic inflammatory response tissue injury transcription factor transcriptomics ubiquitin-protein ligase

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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快速适应造血干细胞（HSC）在骨髓中，它扩散并将其分化向髓样谱系。在理解触发这种紧急造血的信号方面出现了重大兴趣程序。但是，终止HSC和恢复组织的这种响应的机制稳态仍然未知。蛋白酶体抑制剂，硼替佐米和E3泛素的临床成功治疗血液疾病的连接酶胶使泛素途径成为真正的目标癌症治疗学。因此，定义了新型E3连接酶在骨髓中的作用并研究其在正常和紧急造血中的特定作用可导致新的治疗干预措施。我们有证明E3泛素连接酶SPOP限制了HSC的炎症激活。在缺席的情况下 SPOP，系统性炎症以未解决的方式进行以及HSC中的持续反应导致致命的表型让人联想到高炎综合征。我们的蛋白质组学/生化研究表明，SPOP通过靶向信号传感器MyD88的限制了炎症蛋白酶体依赖性降解。 MyD88与炎症刺激导线结合对于myddosome组，IRAK4激酶的高磷酸化和许多激活转录因子途径（NF-KB，JUN，PU.1，CEBPB）。该建议定义：（a）转录和在开始和终止紧急造血作用期间施加的染色质景观变化骨髓HSC和祖细胞，（b）myddosome组装，信号传导和终止的作用在紧急造血和基因调节中，以及（c）myddosome组装和终止。该赠款提案的发现将发现HSC内部机制对于紧急造血后，重新建立体内平衡。