线粒体功能障碍在MDS造血干细胞老化中作用的研究

Myelodysplastic syndrome(MDS) is a clonal hematopoietic stem cells (HSCs) originated malignancy. It is characterized by abnormal hematopoiesis, more apoptosis , genetic instability and has a high risk to transform to acute leukemia. MDS HSCs exibit properties of ageing HSCs characterized as diminished self-renewal repopulation capacity, lineage shewing towards myeloid and hyper apoptosis . Our group perviously has shown that mice deficient of mammalian diaphanous-related formin 1(mDia1) develop a disease that closely resembles human MDS. The mDia1 deficient HSCs is obviously characterized as "ageing stem cells" . And this ageing phenotype is highly related to elevated oxidatative phosphorylation, excess ROS and decreased mitochondrial membrane potential. RNAseq analyse showed the transcriptome of oxidatative phosphorylation pathway in MDS HSCs is up-regulated. Based on the previous results, this project is going to investigate the mitochondrial function and metabolic signal pathway of MDS HSCs, to confirm the regulation role of cytoskeleton to mitochondria, to elucidate the molecular mechanisms whereby mitochondria regulated HSC ageing and pathogenesis of MDS, and provides new and effective therapeutic intervention to rescue the ageing phenotype of human MDS.

骨髓增生异常综合征（MDS）是一种源于造血干细胞（HSCs）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转化为急性白血病。MDS HSCs呈现为“老化”的特征性功能异常，如自新功能下降，偏向髓系分化及高凋亡等。在课题组前期研究中，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HSCs显著表现为“老化”干细胞特点。其线粒体氧化磷酸化代谢增强，ROS增多，膜电位下降，RNAseq检测发现MDS HSCs 线粒体氧化磷酸化代谢通路基因上调。基于此，本课题拟通过进一步检测MDS HSCs线粒体功能及代谢，明确细胞骨架对线粒体生物学特性的调控，并探讨线粒体功能障碍导致MDS HSCs 老化的分子途径。同时，拟观察MDS不同亚型、不同表观遗传特点下线粒体功能及代谢障碍特点，寻找关键老化效应分子，为逆转MDS HSCs老化、治疗MDS提供思路。

骨髓增生异常综合征（MDS）是源于造血干细胞（HSCs）的衰老相关疾病，细胞骨架调节蛋白mDia1定位于5q3.1，敲除mDia1的小鼠高度类似人MDS-5q-表型。前期研究发现mDia1-/-HSCs具有显著老化干细胞特征：脱离“静息”，朝向髓系分化“偏倚”，重建造血能力下降。进一步研究发现，mDia1-/-HSC细胞内ROS升高，单细胞RNA测序结果显示，MDS干细胞（HSCs）线粒体氧化磷酸化（OXPHOS）增强，mTOR通路活化，线粒体裂变重要调控分子Drp-1下降。有趣的是，当给予 NAC降低ROS产生，HSCs 老化表型可部分逆转。以上结果提示ROS过量及线粒体代谢异常促进HSCs衰老，而细胞骨架障碍导致线粒体稳态失衡可能是疾病发生的重要机制。本项目聚焦于细胞骨架调控蛋白mDia1，将线粒体代谢、HSCs老化相结合，为阐明较低危MDS的发病机制及靶向干预提供研究基础及理论依据。