Role of Secreted frizzled-related Protein 1 (Sfrp 1) in the function of the hematopoietic niche

分泌型卷曲相关蛋白 1 (Sfrp 1) 在造血生态位功能中的作用

• 批准号: 246078383
• 负责人: Professor Dr. Robert A.J. Oostendorp
• 金额: --
• 依托单位: Klinik und Poliklinik für Innere Medizin III: Hämatologie und Onkologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/246078383?language=en
• 关键词: Role; Secreted; frizzled; related; Protein

Hematopoietic stem cells (HSCs) reside in a specific niche within the bone marrow that is critical for maintaining these cells under steady state and stress conditions. We have shown that HSCs and stromal cells interact, whereby the niche is stimulated to produce factors which prevent HSC senescence and exhaustion. Interestingly, knockdown of secreted frizzled-related protein 1 (Sfrp1) causes senescence of stromal cells, which do not properly maintain HSCs. Interestingly, downregulation of Sfrp1 activates stromal p53 and its targets. In this research proposal, we will exploit stromal cells in which expression of Sfrp1 is knocked down and identify key nodes in the p53 pathway determining the niche signals regulating HSCs using gene editing. We further aim to dissect the mechanisms of HSC dysregulation in vivo using a conditional Sfrp1flox/flox deletion model generated in the lab. Preliminary experiments in Osx-Cre-driven Sfrp1 deletion mutants show that stromal cells from these mice express markers of senescence. Thus, we will investigate the role of niche senescence and the involvement of p53 and its targets in HSC regulation in vivo, and also determine whether p53 inhibition rescues the defective hematopoiesis in Sfrp1-deficient animals. In the second part of this project, the niche dependence of BCR-ABL+ leukemic cells will be investigated. We found that the Sfrp1-deficient environment forms leukemic cells with different self- renewal and cell fate decisions than those formed in a WT environment. Here, we will assess whether and how defective niche function in the Sfrp1-deficient environment determines alterations in leukemogenesis on a clonal level, and whether this affects therapeutic success. Thus, we will identify key Sfrp1- and p53-dependent pathways involved in niche function and how those regulate HSC and leukemia.

造血干细胞（HSC）存在于骨髓内的特定小生境中，这对于在稳态和应激条件下维持这些细胞至关重要。我们已经表明，HSC和基质细胞相互作用，从而刺激小生境产生防止HSC衰老和衰竭的因子。有趣的是，敲低分泌型卷曲相关蛋白1（Sfrp 1）会导致基质细胞衰老，而基质细胞不能正常维持HSC。有趣的是，Sfrp 1的下调激活基质p53及其靶点。在这项研究提案中，我们将利用Sfrp 1表达被敲低的基质细胞，并使用基因编辑来识别p53途径中决定调节HSC的生态位信号的关键节点。我们进一步的目的是解剖HSC失调的机制，在体内使用的条件Sfrp 1flox/flox删除模型在实验室中产生的。Osx-Cre驱动的Sfrp 1缺失突变体的初步实验表明，这些小鼠的基质细胞表达衰老标记。因此，我们将调查的作用，生态位衰老和参与的p53及其目标在体内HSC的调节，并确定是否p53抑制拯救缺陷的造血Sfrp 1缺陷的动物。在本项目的第二部分，将研究BCR-ABL+白血病细胞的生态位依赖性。我们发现Sfrp 1缺陷环境形成的白血病细胞与WT环境中形成的白血病细胞相比具有不同的自我更新和细胞命运决定。在这里，我们将评估是否以及如何在Sfrp 1缺陷的环境中有缺陷的小生境功能决定白血病发生的改变在克隆水平上，这是否会影响治疗的成功。因此，我们将确定关键的Sfrp 1和p53依赖的途径参与生态位功能，以及如何调节HSC和白血病。