重型β地中海贫血骨髓移植受体干细胞清除机制的研究

项目名称： 重型β地中海贫血骨髓移植受体干细胞清除机制的研究

项目编号： No.U1401221

项目类型： 联合基金项目

立项/批准年度： 2015

项目学科： 管理科学

项目作者： 刘启发

作者单位： 南方医科大学

项目金额： 244万元

中文摘要： 重型β地贫是我国南方区域性高发的严重遗传性血液病，骨髓移植是目前临床治愈该病的唯一方法。我们前期获得国际公认的\骨髓移植治疗新方案和预实验证明预处理使受体造血干细胞（HSC）清除是移植成功的关键问题。本项目首先以重型β地贫小鼠为对象，通过对我们首创的环磷酰胺（Cy）和白消安（Bu）预处理协同作用的研究，揭示受体HSC清除的细胞和分子机制，阐述HSC动员和造血重建细胞反应过程动力学及其变化规律；并阐明实验动物个性化预处理的给药剂量。进一步将上述预处理研究结果通过大样本临床队列研究进行评估，获得相关技术标准的评价结果。以β地贫为代表的富细胞性骨髓的受体干细胞清除机制的阐明，以及个性化预处理标准的建立，可为降低移植排斥率奠定理论基础，并为进一步提高和稳定重型β地贫的移植成功率提供临床治疗规范性技术指南。本研究所获得的新知识，也可为骨髓移植治疗在包括白血病在内的其它血液病的临床应用提供有用的借鉴。

中文关键词： β-地中海贫血；移植；干细胞；清除

英文摘要： β-thalassemia is a group of inherited blood disorders caused by reduced or absent synthesis of the beta chains of hemoglobin resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. It has extremely high incidence in south China area. We have previously established novel preconditioning regimen to vacate bone marrow niche and have obtained significant clinical outcome in hematopoietic stem cell transplantation (HSCT), which has been considered the definitive treatment for Beta-thalassemia patients. Since efficient pre-conditioning to vacate BM niche for the incoming donor HSC is still the hallmark of the success of HSCT due to the excessive proliferative rate of the defect HSCs in β-thalassemias, the proposal will employ -thalassemia mice and study the newly established pre-conditioning regimen using Cyclophosphamide (Cy ) and Busulfan（Bu）to test the cellular and biological basis of BM niche opening in HSCT and wrap-up HSC, therefore understand the kinetics of HSC mobilization and HSC reconstitution. Furthermore, the proposed study will shed light to the determination of clinical dosage in personalized therapy. For the long-term aim, we will move to clinical trial based on the outcome of the study and determine clinical parameters for developing the accurate evaluation criteria of the clinical therapy. The current proposal using β-thalassemias model not only studies the mechanistic link between the novel preconditioning regimen and BM niche vacation but also aim to establish clinical parameters for personalized clinical therapy therefore reduce the incidence of transplantation rejection. In conclusion, the insight gained from the study helps the understanding of clinical HSCT for hematological malignancies, including leukemia and may be applied to direct the future therapy for these diseases.

英文关键词： β-thalassemia;transplantation;hematopoietic stem cell;niche opening