The impact of endothelial restricted hypoxia pathway proteins (PHD2 and endoglin) on the hematopoietic system and its bone marrow niche

内皮限制性缺氧途径蛋白（PHD2和内皮糖蛋白）对造血系统及其骨髓生态位的影响

• 批准号: 418871341
• 负责人: Professor Dr. Ben Wielockx, Ph.D.
• 金额: --
• 依托单位: Institut für Klinische Chemie und Laboratoriumsmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/418871341?language=en
• 关键词: impact; endothelial; restricted; hypoxia; pathway

Sufficient oxygen pressure is required for our organs to function properly. Conversely, insufficient oxygen supply (hypoxia) is a prominent feature in various physiological and pathological processes. The central mediators during deprived oxygen pressure are hypoxia inducible factors (HIFs), whereas their downstream effects are tightly regulated by oxygen-dependent HIF prolyl hydroxylases (PHDs). For this grant proposal, we collected robust sets of preliminary data revealing central roles for endothelial PHD2 and endoglin, in maintaining the integrity of the BM niche and the hematopoietic stem cell (HSC) compartment. In a first aim, we will further characterize the loss of EC-PHD2 and evaluate its effect on bone metabolism, vessel stability and maintenance of the HSC compartment under steady state conditions and after non-lethal irradiation stress. In a second aim, we will unravel the intriguing and protective role of EC-restricted endoglin/CD105 in controlling the HSC compartment and its BM niche. This project will not only provide novel insights into the role of hypoxia pathway proteins in the bone/BM endothelial cells and its interaction with the BM environment; our findings will also raise awareness when it comes to the use of broad spectrum PHD inhibitors to treat patients.

我们的器官需要足够的氧气来正常工作。相反，氧供应不足（缺氧）是各种生理和病理过程的突出特征。缺氧诱导因子（HIF）是缺氧过程中的中枢调节因子，其下游作用受氧依赖性HIF脯氨酰羟化酶（PHDs）的调控。对于这项资助提案，我们收集了一组可靠的初步数据，揭示了内皮PHD 2和内皮糖蛋白在维持BM生态位和造血干细胞（HSC）区室的完整性方面的核心作用。在第一个目标中，我们将进一步表征EC-PHD 2的损失，并评估其在稳态条件下和非致死性辐射应激后对骨代谢、血管稳定性和HSC隔室维持的影响。在第二个目标中，我们将揭示EC限制性endoglin/CD 105在控制HSC隔室及其BM生态位中的有趣和保护作用。该项目不仅将为缺氧途径蛋白在骨/BM内皮细胞中的作用及其与BM环境的相互作用提供新的见解;我们的研究结果还将提高人们对使用广谱PHD抑制剂治疗患者的认识。