sfxn1调控造血干细胞发生和红细胞成熟的分子机制研究

We have identified a missense mutation in the sideroflexin1 (sfxn1) gene in a patient who was suffering from sideroblastic anemia. Sfxn1, also named tricarboxylate carrier protein, may function as a transporter of some ingredients which are advantageous to the iron usage into the mitochondrial. However, until now, we still know very little about its function. In our previous work, we generated sfxn1 loss-of-function mutants in zebrafish through Crispr-cas9 genome editing technology. Homozygous mutant zebrafish exhibited a dramatic reduction in the number of HSPCs and an obvious inhibition of maturation of red blood cells. All the above results suggested that sfxn1 play a critical role during the early development of HSPCs and red blood cell maturation. Based on these preliminary data, we plan to characterize the defects of HSPCs development and red blood cell maturation in the homozygous mutant sfxn1 zebrafish, reveal the molecular regulatory mechanisms and the whole signal network. Our final goals are elaborating the comprehensive and systematic molecular basis of sfxn1 during early hematopoiesis, expanding the novel ideas and methods in the SA and other HSPCs related diseases research, diagnosis, prevention and treatment.

我们在临床样本中发现一例sideroflexin1 (sfxn1)错义突变导致铁粒幼红细胞性贫血的患者。sfxn1也称为三羧酸盐转运蛋白，可能具有转运有利于铁利用的某种成分进入线粒体的功能。但到目前为止，对于sfxn1的具体功能知之甚少。我们利用Crispr-cas9技术成功构建了sfxn1敲除的斑马鱼模型，其纯合突变体的造血干细胞数目显著减少，红细胞成熟明显受到抑制。以上研究表明sfxn1在造血干细胞发生和红细胞成熟过程中发挥关键的调控作用。在此工作基础上，我们拟进一步鉴定sfxn1缺失对造血干细胞发生和红细胞成熟的影响，并对其分子调控机制和整体信号网络进行深入解析，旨在更全面系统地认识sfxn1信号通路介导的造血调控机制，进而发掘和拓展铁幼粒红细胞贫血以及其它遗传性血液干细胞疾病研究、预防和诊治的新思路和方法。

我们在前期临床样本中发现一例sideroflexin1 (sfxn1)错义突变导致的铁粒幼红细胞性贫血的患者，到目前为止，对于sfxn1的具体功能知之甚少。我们利用Crispr-cas9技术成功构建了sfxn1敲除的斑马鱼模型，其纯合突变体的造血干细胞数目显著减少，红细胞成熟明显受到抑制。在此工作基础上，我们进一步鉴定sfxn1缺失对造血干细胞发生和红细胞成熟的影响，并对其sfxn1通过调控血红素的生成来调控红细胞的成熟分子调控机制就行了详细的探索，该基因功能的揭示为全面系统地认识sfxn1信号通路介导的造血发生调控机制，为发掘铁幼粒红细胞贫血疾病的研究、预防和诊治的新思路和方法。