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

我们的器官需要足够的氧压才能正常运作。相反，供氧不足(缺氧)是各种生理和病理过程中的一个显著特征。缺氧压力下的中枢介质是低氧诱导因子(HIF)，而它们的下游作用受氧依赖的HIF脯氨酸羟基酶(PhDS)的严格调控。对于这项拨款提案，我们收集了一组稳健的初步数据，揭示了内皮PHD2和endoglin在维持骨髓壁龛和造血干细胞(HSC)隔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-PHD2的缺失，并评估其在稳态条件下和非致死性辐射应激后对HSC室的骨代谢、血管稳定性和维持的影响。在第二个目标中，我们将揭开EC限制性endoglin/CD105在控制HSC间隔室及其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/骨髓内皮细胞中的作用及其与骨髓环境的相互作用提供新的见解；我们的发现还将提高人们对使用广谱PHD抑制剂治疗患者的认识。

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.