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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

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