DEK Regulation of Hematopoietic Stem Cell Renewal, Fate, and Hematopoiesis

DEK 对造血干细胞更新、命运和造血的调节

• 批准号: 9476237
• 负责人: HAL E. BROXMEYER
• 金额: $ 49.9万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9476237
• 关键词: Affect; Age; Air; Apoptotic; Biochemical; Biological; Biology; Blood Cells; CXCL2 gene; Cell Count; Cell Cycle; Cell Proliferation; Cell physiology; Cells; Chemotaxis; Chromatin; Chromatin Loop; Chromatin Structure; Clinical; DNA; DNA Binding; DNA Repair; Data; Development; Differentiation and Growth; Dipeptidyl-Peptidase IV; Disease; Engraftment; Epigenetic Process; Equilibrium; GTP-Binding Proteins; Gene Expression; Gene Expression Profiling; Growth Factor; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Heterochromatin; Homeostasis; Homing; Human; Hypoxia; IL8 gene; IL8RB gene; In Vitro; Interleukin-8; Link; Malignant - descriptor; Mediating; Metabolism; MicroRNAs; Modification; Molecular; Molecular Genetics; Mus; Non-Malignant; Nuclear; Nuclear Protein; Oncoproteins; Organ; Oxygen; Patients; Pertussis Toxin; Phenotype; Physiological; Play; Population; Process; Proteins; Recombinants; Recovery; Regulation; Reporting; Role; S Phase; Shock; Signal Transduction; Stress; T-Lymphocyte; Testing; Text; Work; aptamer; chemokine receptor; cytokine; enhancing factor; experimental study; extracellular; genome-wide; genome-wide analysis; hematopoietic cell transplantation; hematopoietic stem cell fate; improved; in vivo; inhibitor/antagonist; interdisciplinary approach; monocyte; mouse model; non-histone protein; novel strategies; paracrine; public health relevance; receptor; self-renewal; stem; stem cell division; subcutaneous; uptake

 DESCRIPTION (provided by applicant): Elucidating the mechanisms by which hematopoietic stem cell renewal and lineage differentiation are controlled is crucial to improving hematopoietic recovery after stress and hematopoietic cell transplantation. Recently, we discovered that the biochemically distinct and unique DEK protein is a factor that enhances ex-vivo expansion of hematopoietic stem cells (HSCs) and HSC engraftment, while regulating hematopoietic progenitor cell (HPC) proliferation and cycling though its interaction with the CXCR2 chemokine receptor. While DEK has been implicated in multiple intranuclear activities, we have recently found that this non-histone protein with no enzymatic activity modulates global heterochromatin integrity and hence gene expression. Interestingly, in addition to its intranuclear functions, we have found that DEK can be secreted by monocytic cells and released by apoptotic T cells, and act as a chemotactic factor for neutrophils, as well as for HSCs and HPCs, through a mechanism involving CXCR2, which also mediates at least some of DEK's effects on the cycling of HPCs. Remarkably, we have now also discovered that the intranuclear and extracellular functions of DEK can be unified, as extracellular DEK can be taken up by several different types of hematopoietic and other cells in a bioactive form that modulates chromatin structure and DNA repair. Thus, DEK is a nuclear protein that regulates hematopoiesis and participates in a highly unusual loop involving secretion, receptor engagement, uptake, and subsequent modulation of heterochromatin biology, gene expression and HSC/HPC functions. Strikingly, this loop is active in vivo, as subcutaneous administration of recombinant DEK to mice leads to significant increases in phenotyped HSCs and lower numbers and decreased cycling of HPCs. Therefore, we propose to use a multidisciplinary approach to test the hypothesis that this intranuclear/extracellular loop involving DEK plays a significant role in hematopoietic growth and differentiation and stem engraftment by affecting chromatin balance and CXCR2-mediated signaling. Using immature subsets of mouse and human hematopoietic cells, mouse models of homeostasis and stressed hematopoiesis, cell signaling studies, epigenetic analysis, and genome-wide studies of chromatin structure and gene expression, we will further delineate the mechanisms by which DEK modulates the fate decisions between HSC proliferation, survival, self-renewal and differentiation and promotes HSC engraftment in vivo. The proposed experiments will elucidate how DEK works through CXCR2 signaling and the highly unusual extracellular/intracellular chromatin loop to affect HSC fate decisions and hematopoiesis. This will be done in context of Dipeptidylpeptidase (DPP) 4 modification of DEK, and the influence of extra physiologic oxygen shock/stress on DEK functions in vivo and in vitro. These studies have the potential to generate new approaches to the treatment of hematopoietic disorders and other diseases in which hematopoietic cell transplantation is required.

 说明（由申请人提供）：阐明造血干细胞更新和谱系分化的控制机制对于改善应激和造血细胞移植后的造血恢复至关重要。最近，我们发现生物化学上独特且独特的DEK蛋白是增强造血干细胞（HSC）的离体扩增和HSC植入的因子，同时通过其与CXCR 2趋化因子受体的相互作用来调节造血祖细胞（HPC）增殖和循环。虽然DEK已被牵连在多个核内活动，我们最近发现，这种非组蛋白蛋白没有酶活性调节全球异染色质的完整性，因此基因表达。有趣的是，除了其核内功能之外，我们已经发现DEK可以由单核细胞分泌并由凋亡T细胞释放，并且通过涉及CXCR 2的机制作为中性粒细胞以及HSC和HPC的趋化因子，CXCR 2也介导DEK对HPC循环的至少一些影响。值得注意的是，我们现在还发现DEK的核内和细胞外功能可以统一，因为细胞外DEK可以以调节染色质结构和DNA修复的生物活性形式被几种不同类型的造血细胞和其他细胞摄取。因此，DEK是一种调节造血的核蛋白，并参与一个非常不寻常的环，涉及分泌、受体接合、摄取和随后的异染色质生物学、基因表达和HSC/HPC功能的调节。引人注目的是，该环在体内是活跃的，因为向小鼠皮下施用重组DEK导致表型化HSC的显著增加和HPC的数量减少和循环减少。因此，我们建议使用多学科的方法来测试这一假设，即涉及DEK的核内/细胞外环通过影响染色质平衡和CXCR 2介导的信号传导在造血生长和分化以及干细胞移植中起着重要作用。利用小鼠和人类造血细胞的未成熟亚群，稳态和应激造血的小鼠模型，细胞信号传导研究，表观遗传学分析，以及染色质结构和基因表达的全基因组研究，我们将进一步阐明DEK调节HSC增殖，存活，自我更新和分化之间的命运决定的机制，并促进HSC体内植入。拟议的实验将阐明DEK如何通过CXCR 2信号传导和极不寻常的细胞外/细胞内染色质环影响HSC命运决定和造血。这将在二肽基肽酶（DPP）4修饰DEK以及额外生理性氧休克/应激对体内和体外DEK功能的影响的背景下进行。这些研究有可能产生新的方法来治疗造血系统疾病和其他需要造血细胞移植的疾病。