Adhesion GPCR signaling in hematopoietic stem and progenitor cells

造血干细胞和祖细胞中的粘附 GPCR 信号传导

• 批准号: 393657104
• 负责人: Dr. Caroline Pabst
• 金额: --
• 依托单位: Klinik für Hämatologie, Onkologie und Rheumatologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/393657104?language=en
• 关键词: Adhesion; GPCR; signaling; hematopoietic; stem

Knowledge about the differences and similarities between normal and malignant hematopoietic stem and progenitor cells (HSPCs) is crucial for the development of more efficacious anti-leukemic therapeutic approaches. We recently identified the adhesion G protein-coupled receptor ADGRG1/GPR56 as a novel marker discriminating the leukemia stem cell (LSC) compartment from non-LSC blasts in acute myeloid leukemia. We found evidence that besides from being a marker for leukemic stem cells GPR56 might also play a crucial role for the in vitro and in vivo function of normal HSPCs, as GPR56 knockdown severely reduced colony formation and engraftment capacity of CD34+ cord blood cells.Analysis of RNA Sequencing data of multiple hematopoietic populations sorted from normal bone marrow revealed that several other adhesion GPCRs show distinct expression patterns in immature and differentiated bone marrow cell populations similar to GPR56. We therefore hypothesize that adhesion GPCR signaling via GPR56 and other aGPCRs is tightly regulated by intrinsic and extrinsic factors controlling self-renewal and differentiation. To approach this hypothesis we will dissect GPR56 signaling in the hematopoietic system using a Gpr56 inducible knockout model, and by performing structure-function analyses in primary human HSPCs. In an independent approach, we will identify whether other aGPCRs with similar expression patterns in human HSPCs compared to GPR56 have non-redundant functional roles in the hematopoietic system. Knowledge gained from these experiments will lead to a better understanding of adhesion GPCR signaling in the hematopoietic system and will elucidate whether aGPCRs might represent suitable therapeutic targets.

了解正常和恶性造血干细胞和祖细胞（HSPCs）之间的异同对于开发更有效的抗白血病治疗方法至关重要。我们最近发现了粘附G蛋白偶联受体ADGRG1/GPR56作为急性髓系白血病中区分白血病干细胞（LSC）室和非LSC母细胞的新标志物。我们发现证据表明，GPR56除了作为白血病干细胞的标志物外，还可能对正常造血干细胞的体外和体内功能起关键作用，因为GPR56敲低严重降低了CD34+脐带血细胞的集落形成和植入能力。从正常骨髓中提取的多个造血群体的RNA测序数据分析显示，其他几种粘附gpcr在未成熟和分化的骨髓细胞群体中表现出不同的表达模式，类似于GPR56。因此，我们假设通过GPR56和其他agpcr的粘附GPCR信号受到控制自我更新和分化的内在和外在因素的严格调控。为了实现这一假设，我们将使用GPR56诱导敲除模型，并通过对原代人HSPCs进行结构-功能分析，解剖造血系统中的GPR56信号。在一种独立的方法中，我们将确定与GPR56相比，在人类HSPCs中具有相似表达模式的其他agpcr是否在造血系统中具有非冗余的功能作用。从这些实验中获得的知识将有助于更好地理解造血系统中的粘附GPCR信号，并将阐明agpcr是否可能代表合适的治疗靶点。