miRNAs是一类小分子非编码RNA，可以调控特定靶基因表达，在造血过程中起重要作用。miR-144/451是一个受转录因子GATA-1调控的双顺反子位点，是目前发现的成熟红细胞中表达最高的miRNAs。我们敲除该位点后发现，小鼠红细胞的抗氧化能力明显下降。我们最近发现miR-144/451敲除鼠还出现幼红细胞凋亡增加，成熟受阻和线粒体生物合成异常等其它造血功能障碍。本课题计划利用miR-144/451敲除鼠作为体内模型，给合胚胎造血干细胞培养等体外系统，确定miR-144/451是否通过抑制其靶基因Cab39、Ywhaz、Myc、Rac1及相关发育途径调节正常和应激造血时红细胞存活、分化、线粒体生物合成和氧化磷酸化功能，旨在找出调节红系生成新途径并确定它们与人类病理状态（急性溶血性贫血、肿瘤化疗毒副作用、急性失血）的相关性，为红系疾病治疗新靶点提供理论依据。

MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of specific target genes and play important roles in hematopoiesis. miR-144 and miR-451 are encoded in a bi-cistronic gene locus that is activated by the transcription factor GATA-1 and are the most abundantly expressed miRNAs in mature red blood cells. We knocked out miR-144/451 and found that erythroid cells from miR-144/451-/- mice exhibit reduced anti-oxidative response and enhanced susceptibility to oxidative stress. Our new preliminary data indicates that miR-144/451-/- mice exhibit increased erythroid apoptosis, maturation block, and increased biogenesis of mitochondria and oxidative phosphorylation. This proposal describes plans for more extensive study on the role of miR-144/451 in erythropoiesis. We will focus on miR-144/451 knockout mice we generated as an in vivo model and utilize in vitro systems including fetal liver-derived hematopoietic stem cell culture to examine whether miR-144/451 regulates erythroid survival, maturation, biogenesis of mitochondria and oxidative phosphorylation by targeting Cab39, Ywhaz, Myc，Rac1 and related developmental pathways under both baseline and stress conditions. Our goal is to map the molecular pathways through which miR-144/451 regulates normal erythropoiesis and to determine their relevance for human disease conditions such as acute hemolytic anemia, toxic side effect of cancer chemotherapy and acute blood loss.