The effect of glucocorticoid excess on the osteohematopoietic niche

糖皮质激素过量对骨造血生态位的影响

• 批准号: 415012230
• 负责人: Dr. Ulrike Baschant
• 金额: --
• 依托单位: Medizinische Klinik und Poliklinik III
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/415012230?language=en
• 关键词: effect; glucocorticoid; excess; osteohematopoietic; niche

Glucocorticoids (GCs) are potent immunosuppressive drugs exerting anti-inflammatory effects through complex actions on circulating immune cells as well as tissue-specific cells. However, long-term GC treatment causes severe side effects such as GC-induced osteoporosis due to adverse actions of GCs in mesenchymal tissues. GCs exert their effects mainly via the glucocorticoid receptor (GR) that regulates gene expression. Despite the known suppressive impact of GCs on immune cells, GC actions in the osteohematopoietic niche remain ill-defined. Thus, we aim to explore the effects of long-term GC treatment on hematopoietic stem cell (HSC) function. In preliminary investigations of GC-treated GR deficient mice, we found a reduced cell number in the bone marrow as well as a reduction of HSCs in GR-sufficient mice but not in GR-deficient mice. Furthermore, the potential of HSCs derived from bone marrow to differentiate into the various hematopoietic lineages was impaired upon long-term GC treatment. Thus, we hypothesize that long-term GC exposure affects HSC numbers, viability and function in a GR-dependent manner. Therefore, we aim to explore the effects and molecular mechanisms of GC treatment on the cellular constituents of the osteohematopoietic niche. We aim to thoroughly assess GC effects on HSC function and the cellular compartments of the niche by bone marrow transplantation studies and flow cytometric analysis. In addition, we will use genetically modified GR-mouse models to delineate the cellular targets of GCs within the bone marrow compartment utilizing immuno- and histologic investigations, gene expression analyses and ex vivo approaches. Finally we will characterize molecular pathways affected by GCs within target cells in an unbiased omics-approach on genome and protein level. Our results will provide significant insights to the molecular effects of GCs on HSCs. Dissecting the mechanisms involved could lead to the development of strategies to alleviate the deleterious effects of GCs on the osteohematopoietic niche.

糖皮质激素（GC）是一种有效的免疫抑制药物，通过对循环免疫细胞以及组织特异性细胞的复杂作用发挥抗炎作用。然而，由于GC在间充质组织中的不良作用，长期GC治疗会导致严重的副作用，例如GC诱导的骨质疏松症。GC主要通过调节基因表达的糖皮质激素受体（GR）发挥其作用。尽管已知GC对免疫细胞的抑制作用，但GC在造血小生境中的作用仍然不明确。因此，我们的目的是探讨长期GC治疗对造血干细胞（HSC）功能的影响。在GC处理GR缺陷小鼠的初步研究中，我们发现骨髓中的细胞数量减少以及GR充足小鼠中的HSC减少，但GR缺陷小鼠中没有。此外，长期GC治疗后，源自骨髓的HSC分化为各种造血谱系的潜力受到损害。因此，我们假设长期GC暴露以GR依赖的方式影响HSC数量、活力和功能。因此，我们的目的是探讨GC治疗对骨造血生态位的细胞成分的影响和分子机制。我们的目的是通过骨髓移植研究和流式细胞术分析，彻底评估GC对HSC功能和细胞区室的影响。此外，我们将使用遗传修饰的GR-小鼠模型来描绘GC的细胞靶点，利用免疫和组织学研究，基因表达分析和离体方法在骨髓隔室。最后，我们将在基因组和蛋白质水平上以无偏组学方法表征靶细胞内受GC影响的分子途径。我们的研究结果将为GCs对HSC的分子作用提供重要的见解。剖析所涉及的机制可能导致发展战略，以减轻有害影响的GCs的骨造血生态位。