miR-155参与调控巨核细胞增殖分化与DS-AMKL发病机制研究

Down syndrome (DS) is caused by trisomy of all or part of human chromosome 21 (HSA21). Overexpression of the genes on HSA21 because of the effect of gene dosage is considered to be one of the main reasons for DS phenotypes.In children with Down syndrome (DS), the risk of developing acute megakaryocytic leukemia (AMKL) is estimated at 500 times higher than in children without DS. MicroRNAs (miRNAs) are a class of evolutionarily conserved, single-stranded non-coding RNA molecules that control gene expression at a post-transcriptional level. miR-155 is located in human chromosome 21 and overexpressed in many tissues of DS patients. Recent studies strongly implicate miR-155 in the process of proliferation and differentiation of megakaryocyte. While solid evidences have proved that the deregulation of miR-155 is linked to pathological myeloid proliferations， there is no report on the relationship between the overexpression of miR-155 and the increased risks of AMKL in DS.The applicant constructed a DS mouse model, which shows abnormal proliferation and differentiation of megakaryocyte. In this project, we will use this mouse model and a miR-155 gene knock-out mouse to produce DS mouse models with different miR-155 copy numbers. We will analyze the differences in the aspect of proliferation and differentiation of megakaryocyte between the DS mouse model with 3 copies of miR-155 and the DS mouse model with 2 copies of miR-155. By this way, we could identify the effect of gene dosage of miR-155 on hemopoiesis in DS. We would also check the effect of different miR-155 dosage to cytokines,transcription factors and MAPK signal pathway that are considered to be related to the differentiation and proliferation of megakaryocyte. MiRNAs exert their biological functions through the degradation and/or translational repression of target mRNAs. We would confirm the function of miR-155 target mRNAs in the proliferation and differentiation of megakaryocyte, so to clarify the possible ways by which the miR-155 regulates the hematopoiesis and explore the mechanism of DS-AMKL. We would also try to down-regulate the miR-155 level in DS mice by using miRNA inhibitor to find possible cure targets for AMKL both in DS and normal people.

唐氏综合征（DS）患者中急性巨核细胞白血病（AMKL）发病率比正常人中高出约500倍，其机制不明。位于人21号染色体上的miR-155在DS中有三个拷贝，在DS病人多个组织中过量表达。大量证据表明miR-155在调控巨核细胞增殖分化中发挥重要作用，其异常表达会引起AMKL的早期症状即巨核细胞异常增殖分化，但其过量表达与DS-AMKL是否直接相关仍未见报道。本研究拟使用DS模型鼠和miR-155基因敲除鼠，构建含不同miR-155拷贝数的DS小鼠，比较这些DS小鼠巨核细胞增殖分化的异同，从而确证不同miR-155基因剂量对DS巨核细胞增殖及分化的影响及其在DS-AMKL中的地位和作用。本研究还将从巨核细胞增殖分化的分子机制入手，结合miR-155靶mRNA研究以探索其影响巨核细胞增殖分化的分子机理。本研究也致力于为DS及正常人群中AMKL提供可能的治疗靶点。

在唐氏综合症（DS）患儿中，白血病发病风险较高，其中以急性巨核细胞白血病(AMKL)最为显著。DS相关的AMKL（DS-AMKL）发病机制尚不明了，在DS小鼠模型中检测到了DS-AMKL的前期症状即巨核细胞异常增殖，然而，致病基因并不明确。本项课题首先利用miR-155基因敲除小鼠结合DS小鼠研究了miR-155对小鼠造血细胞增殖分化的影响，发现miR-155过量表达是DS小鼠外周血中红系数量减少的重要原因，但与巨核细胞增殖关系不大；miR-155过量表达导致TPO信号传导途径相关蛋白STAT3过量表达可能是外周血异常的重要原因。此外，研究者与美国合作单位共同构建了gata1基因部分敲除小鼠，对该小鼠结合DS小鼠模型Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+研究表明，gata1基因部分缺失造成类似外周血异常，包括红细胞数量减少，巨红细胞症，巨核细胞增生等，但gata1基因部分缺失与DS对小鼠外周血异常并无协同效应。

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