G-CSF receptor in progenitor mobilization

描述（由申请人提供）：本研究的长期目标是表征调节造血祖细胞（HPC）从骨髓向血液动员的机制。造血干细胞移植是治疗晚期血液系统恶性肿瘤的一种有效方法。最近，动员的外周血HPC代替骨髓来源的HPC已被使用，因为减少了植入时间和相对容易的收集。目前的动员方案，利用粒细胞集落刺激因子（G-CSF）单独通常是耐受性良好，但不是普遍有效的，往往与肿瘤细胞的共动员。更好地了解调节HPC动员的机制可能会导致设计新的动员策略，克服这些问题。 越来越多的证据表明，基质衍生因子-1（SDF-1，CXCL 12）及其同源受体CXCR 4之间的相互作用可能在调节HPC和中性粒细胞从骨髓的运输中发挥关键作用。SDF-1和CXCR 4的功能丧失模型已经确定了这些基因在HPC从胎肝迁移到骨髓中的关键作用。最近，CXCR 4基因的功能获得性突变与WHIM综合征的发病机制有关，WHIM综合征是一种部分表现为骨髓中性粒细胞运输受损的综合征。我们最近发现，G-CSF治疗导致野生型小鼠骨髓中SDF-1 α蛋白显著减少。最后，用CXCR 4的选择性拮抗剂AMD 3100治疗，在小鼠和人类中诱导快速和稳健的HPC动员。总的来说，这些数据表明了一种假设，其中SDF-1/CXCR 4信号传导的破坏是G-CSF动员HPC的关键步骤。本研究的目的是验证这一假设，并确定动员剂调节SDF-1/CXCR 4信号传导的机制。提出了以下具体目标。 1.我们将确定WHIM综合征患者中发现的CXCR 4基因的功能获得性突变是否足以诱导HPC受损和骨髓中性粒细胞转运。 2.我们将确定G-CSF调节骨髓中SDF-1表达的机制。 3.我们将确定SDF-1/CXCR 4信号传导的中断是否是不同动员剂介导HPC动员的共同最终途径。

DESCRIPTION (provided by applicant): The long-range objective of this research is to characterize the mechanisms that regulate the mobilization of hematopoietic progenitor cells (HPC) from the bone marrow to blood. Hematopoietic stem cell transplantation is a potentially curative therapy for patients with advanced hematological malignancies. Recently, mobilized peripheral blood HPC instead of bone marrow-derived HPC have been used because of reduced engraftment times and relative ease of collection. Current mobilization protocols utilizing granulocyte colony stimulating factor (G-CSF) alone are generally well tolerated but not universally effective and are often associated with co-mobilization of neoplastic cells. A better understanding of the mechanisms that regulate HPC mobilization may lead to the design of novel mobilization strategies that overcome these problems. Accumulating evidence suggests that interactions between stromal derived factor-1 (SDF-1, CXCL12) and its cognate receptor, CXCR4, may play a key role in regulating HPC and neutrophil trafficking from the bone marrow. Loss-of-function models for SDF-1 and CXCR4 have established a critical role for these genes in the migration of HPC from the fetal liver to bone marrow. More recently, gain-of-function mutations of the CXCR4 gene have been implicated in the pathogenesis of WHIM syndrome, a syndrome manifested, in part, by impaired neutrophil trafficking from the bone marrow. We recently showed that G-CSF treatment results in a significant decrease in SDF-1alpha protein in the bone marrow of wild type mice. Finally, treatment with AMD3100, a selective antagonist of CXCR4, induces rapid and robust HPC mobilization in mice and humans. Collectively, these data suggest a hypothesis in which disruption of SDF-1/CXCR4 signaling is a key step in HPC mobilization by G-CSF. The objective of this research is to test this hypothesis and define mechanisms by which mobilizing agents regulate SDF-1/CXCR4 signaling. The following specific aims are proposed. 1. We will determine whether gain-of-function mutations of the CXCR4 gene found in patients with WHIM syndrome are sufficient to induce impaired HPC and neutrophil trafficking from the bone marrow. 2. We will identify the mechanisms by which G-CSF regulates SDF-1 expression in the bone marrow. 3. We will determine whether disruption of SDF-1/CXCR4 signaling is a common final pathway by which diverse mobilizing agents mediate HPC mobilization.