骨髓增生异常综合征（MDS）是一种起源于造血干细胞（HSC）的恶性克隆性疾病。临床上MDS以病态造血、凋亡亢进为特征，具有遗传不稳定性易向白血病转化。MDS干细胞生物学特性及其恶性转化机制因缺乏理想的动物模型而成为研究"瓶颈"，缺乏有效的干预措施。在课题前期研究中，细胞骨架调节蛋白mDia1基因敲除小鼠表现为类似人MDS的表型，其HSC显著表现为衰老干细胞特征，如偏向髓系的造血失衡、"自新"（self-renewal）能力下降、异常细胞凋亡、细胞周期加速却异常造血。基于此，本课题拟通过检测衰老调控基因在MDS与正常HSC差异表达，建立衰老HSC基因表达谱，探讨mDia1对HSC衰老的影响。同时，拟观察mDia1对HSC衰老相关信号途径（如p53-p21、Wnt/Gsk3β）调控作用，以寻找关键衰老效应分子，逆转MDS衰老表型，寻求人MDS发病机制及治疗措施。

Myelodysplastic syndrome(MDS)is a clonal hematopoietic stem cell(HSC)originated malignancy. It is characterized by abnormal hematopoiesis, more apoptosis and genetic instability and has a high risk to transform to leukemia. Due to lack of ideal animal model, the investigation of the biological properties and mechanism of malignant transformation of MDS HSCs has became the "bottle neck" in MDS research. So far, no effective therapy has been development for treatment of human MDS. Our group previously has shown that mice deficient for mammalian diaphanous-related formin 1(mDia1) develop a disease that closely resembles human MDS. The mDia1 deficient MDS HSCs exibit properties of aged HSCs, including lineage shewing towards myeloid, diminished self-renewal repopulation capacity,exsausted HSCs with increased entering of G1 phase of cell cycle and apoptosis but non-productive in peripheral blood. In this proposal, we will investigate the effect of mDia1 deficiency on HSCs aging by evaluating the expression of biomarkers of HSC aging and utilizing high-throughput RNA sequencing to analyze the transcriptome of MDS HSCs. In addition, we will investigate the effect of mDia1 deficiency on the activation of aging-related signaling pathways(such as p53-p21,Wnt/GSK3β signal axis). This proposal will further elucidates the molecular mechanisms whereby mDia1 regulated HSC aging and pathogenesis of MDS and provides new and effective therapeutic intevention to rescue the aging phenotype for new treatment of human MDS.