DLK1与骨髓增生异常综合征骨髓衰竭的研究

项目名称： DLK1与骨髓增生异常综合征骨髓衰竭的研究

项目编号： No.81470295

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 肖志坚

作者单位： 中国医学科学院

项目金额： 70万元

中文摘要： 骨髓间充质干细胞（BM-MSC）及其分化的细胞是骨髓微环境的重要组成部分，其参与造血干细胞（HSC）的自我更新，增殖和分化，对造血起着支持和调节作用。近年来对骨髓增生异常综合征（MDS）患者和小鼠模型的研究发现，BM-MSC在细胞生物学、细胞遗传学、表观遗传学方面存在异常。我们的前期研究发现MDS-MSC中DLK1表达量较正常对照和再生障碍性贫血患者明显增高。体外长周期BM-MSC与HSC共培养结果显示过表达DLK1的转基因鼠BM-MSC具有抑制BFU-E，CFU-G，CFU-M增殖的能力。本课题在这些前期研究发现的基础上得以提出，拟通过体内、外实验，应用分子生物学、表观遗传学、细胞生物学和转基因动物模型的实验方法，研究DLK1表达异常对BM-MSC增殖、分化、造血支持、免疫调节功能的影响并建立新的MDS小鼠模型。旨在阐明DLK1在MDS骨髓衰竭中的作用，以期为MDS的治疗寻找新的靶标。

中文关键词： 骨髓增生异常综合征/；MDS；DLK1；骨髓衰竭；骨髓间充质干细胞；造血干细胞

英文摘要： Bone marrow mesenchymal stem cells (BM-MSCs) and their progeny are the main components of the bone marrow microenvironment. Normal haematopoiesis is regulated by BM-MSCs and their progeny, maintaining haemopoietic stem cell (HSC) self-renewal and orchestrating HSC proliferation and differentiation to all blood cell types. Resent studies for myelodysplastic syndrome (MDS) patients and MDS mice model revealed BM-MSC harbored abnormalities in cytobiology, cytogenetics and epigenetics. Our previous study showed that DLK1 mRNA and protein levels were higher in BM-MSCs from MDS patients than those from healthy control and aplastic anemia patients. In vitro, the result of long term co-culture showed that BM-MSCs of transgenic mice which over-expressed DLK1 inhibited the proliferation capacity of BFU-E, CFU-G, CFU-M, besides the size of the colones was much smaller and the morphology seemed looser compared to the controls, especially the BFU-E. In order to explore the impact of DLK1 on bone marrow failure in MDS and new therapeutic targets, using the methods of molecular biology, epigenetics, cytobiology and transgenetic mice model, we will study the impact of DLK1 on BM-MSC proliferation, differentiation, haemopoietic supportive capacity, immunomodulation in vivo and vitro and develop new MDS mice model.

英文关键词： myelodysplastic syndrome;DLK1;bone marrow failure;mesenchymal stem cell;hematopoietic stem cell