Plerixafor for allogeneic hematopoietic stem cell transplantation

Plerixafor 用于同种异体造血干细胞移植

• 批准号: 8190129
• 负责人: Yubin Kang
• 金额: $ 13.16万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-05 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190129
• 关键词: Adrenergic Receptor; Allogenic; Animals; Area; Award; B-Lymphocytes; Binding; Blood Platelets; CD34 gene; CSF3 gene; CXCR4 Signaling Pathway; CXCR4 gene; Caring; Catecholamines; Cell Lineage; Cell Transplantation; Cells; Clinical Trials; Congenic Mice; Disease; Dose; Engraftment; Erythrocytes; Goals; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homing; Human; Incidence; Ligands; Malignant - descriptor; Marrow; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Myeloid Cells; Non-Malignant; Patients; Personal Satisfaction; Phase; Phosphotransferases; Play; Production; Protein-Serine-Threonine Kinases; Publishing; Recombinant Granulocyte Colony Stimulating Factor; Recovery; Regimen; Regulation; Residual state; Role; Schedule; Signal Pathway; Signal Transduction; Staging; Stem cells; Stromal Cell-Derived Factor 1; Surface; Sympathetic Nervous System; T-Lymphocyte; Testing; Toxic effect; Translating; Transplantation; base; chemokine; chemokine receptor; clinical application; conditioning; cytokine; dosage; graft failure; graft vs host disease; improved; insight; interest; mortality; neutrophil; preclinical study; reconstitution; stem cell biology; translational study

DESCRIPTION (provided by applicant): Hematopoietic cell transplantation (HCT) provides a potentially curative treatment for a wide variety of diseases. HCT, however, is complicated by high incidence of transplant-related mortality, graft failure and graft versus host disease (GvHD). The interaction of stromal derived factor-1 (SDF-1) with CXCR4 chemokine receptor plays an indispensable role in hematopoietic stem cell homing and engraftment. We hypothesize that blocking the SDF-1/CXCR4 interaction with a specific CXCR4 antagonist would selectively enhance donor cell reconstitution in allogeneic HCT. Plerixafor is a highly specific and reversible antagonist of CXCR4 and will be used in the current study. Our recent studies in a congeneic mouse transplant model demonstrated that post-transplant administration of plerixafor significantly improved animal survival and selectively enhanced donor cell engraftment. This selective enhancement of donor cell reconstitution results from combined effects of mobilization of residual recipient stem cells by plerixafor and selective survival advantage of donor stem cells. The objectives of this proposal are to perform pivotal translational studies to move our study into a phase I/II clinical trial at the end of this award and to further dissect the mechanisms of plerixafor and the regulation of CXCR4 signaling. We have 2 specific aims. Our Aim 1 is to investigate the efficacy of plerixafor in enhancing donor cell engraftment in several allogeneic mouse transplant models that are directly relevant to clinical applications. Our Aim 2 is to further dissect the mechanisms through which plerixafor enhances donor cell reconstitution and to understand the regulation of CXCR4 signaling. Successful accomplishment of these aims will have important implications in HCT and will benefit patients with HCT. Furthermore, our study will shed new lights into the role of CXCR4 in hematopoietic stem cell homing, mobilization and expansion, as well as the regulation of CXCR4 signaling. PUBLIC HEALTH RELEVANCE: Our study will provide a better understanding of the stem cell biology. Additionally, our study will improve the care and the well-being of patients receiving hematopoietic stem cell transplantation.

描述（由申请人提供）：造血细胞移植（HCT）为多种疾病提供了潜在的治疗方法。然而，HCT因移植相关死亡率，移植失败和移植与宿主疾病（GVHD）的高发生率而变得复杂。基质衍生因子-1（SDF-1）与CXCR4趋化因子受体的相互作用在造血干细胞寄养和植入中起着必不可少的作用。我们假设阻止SDF-1/CXCR4与特定CXCR4拮抗剂的相互作用将有选择地增强同种异体HCT中的供体细胞重建。 Plerixafor是CXCR4的高度特异性和可逆的拮抗剂，将用于当前研究。我们最近在凝聚小鼠移植模型中的研究表明，移植后plerixa用于显着提高动物生存，并有选择地增强了供体细胞的植入。供体细胞重构的选择性增强是由于plerixafor动员干细胞动员的结合作用和供体干细胞的选择性生存优势。该提案的目标是进行关键的翻译研究，以将我们的研究转移到该奖项结束时的I/II期临床试验中，并进一步剖析Plerixafor的机制和CXCR4信号的调节。我们有2个具体目标。我们的目标1是研究Plerixafor在与临床应用直接相关的几种同种异体小鼠移植模型中增强供体细胞植入的功效。我们的目标2是进一步剖析plerixafor增强供体细胞重建的机制，并了解CXCR4信号传导的调节。成功完成这些目标将对HCT产生重要影响，并将使HCT患者受益。此外，我们的研究将使CXCR4在造血干细胞寄养，动员和扩张以及CXCR4信号传导中的作用中发挥新的作用。 公共卫生相关性：我们的研究将更好地了解干细胞生物学。此外，我们的研究将改善接受造血干细胞移植的患者的护理和福祉。