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
• 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
• 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

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.

项目概要 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骨髓谱系。 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 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 用于治疗血液疾病的连接酶胶使泛素途径成为真正的目标 癌症治疗。因此，定义新型 E3 连接酶在骨髓中的功能并研究它们的作用 在正常和紧急造血中的特定作用可以导致新的治疗干预措施。我们有 证明 E3 泛素连接酶 Spop 抑制 HSC 的炎症激活。在缺席的情况下 Spop 的系统性炎症以未解决的方式进行，HSC 的持续反应 导致令人想起高炎症综合征的致命表型。我们的蛋白质组/生化 研究表明，Spop 通过靶向信号转导器 Myd88 来限制炎症 蛋白酶体依赖性降解。 Myd88 积累与炎症刺激相结合导致 Myddosome 的形成、Irak4 激酶的过度磷酸化和许多 转录因子途径（NF-kB、Jun、Pu.1、Cebpb）。该提案定义了：(a) 转录和 紧急造血作用启动和终止过程中染色质景观的变化 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控中以及（c）myddosome组装和的结构细节 终止。这项拨款提案的研究结果将揭示 HSC 的内在机制，这对于 紧急造血后重建体内平衡。