Regulation of erythropoiesis by the miR-144/451 microRNA locus

描述(由申请人提供)：我们寻求发现管理红细胞形成(红细胞生成)的新的、医学上相关的机制。最近发现的小的非编码RNA被称为microRNAs(MiRs)，它深刻地影响着几乎所有组织的正常发育和应激反应。MIRS通过抑制通过Watson-Crick碱基配对识别的特定靶mRNAs的翻译和稳定性来抑制蛋白质合成。这项建议研究了MIR144和451的作用，这两个基因编码在单个基因座位上，在红细胞生成过程中强烈诱导。在斑马鱼和小鼠中，miR-451的缺失损害了红细胞的生成，使成熟的红细胞对氧化应激的破坏变得敏感，并在急性贫血后诱导红系前体细胞凋亡。初步数据表明，miR-144/451通过确认的靶基因Rab14、Myc、Ywhaz和Cab39来调节红细胞生成过程中铁的摄取、存活、成熟和线粒体能量代谢。我们将进一步研究MIR144和451在基线和疾病相关应激期间控制红细胞生成的机制，包括失血、缺铁和不平衡的血红蛋白产生(地中海贫血)。我们的工作应该为红系发育和相关疾病提供新的见解，包括骨髓增生性综合征和各种贫血。此外，通过我们对红细胞生成的研究获得的知识应该适用于miR-451被认为发挥作用的其他生物学过程，包括对心肌应激的保护，免疫反应的调节，以及在许多恶性肿瘤中作为肿瘤抑制因子。

DESCRIPTION (provided by applicant): We seek to discover new, medically relevant mechanisms governing red blood cell formation (erythropoiesis). Recently identified small non-coding RNAs, termed microRNAs (miRs), profoundly influence normal development and stress responses in virtually all tissues. MiRs suppress protein synthesis by inhibiting the translation and stability of specific target mRNAs that are recognized via Watson-Crick base pairing. This proposal investigates the role of miRs 144 and 451, which are encoded on a single gene locus that is strongly induced during erythropoiesis. In zebrafish and mice, loss of miR-451 impairs erythropoiesis, sensitizes mature erythrocytes to destruction by oxidant stress and induces erythroid precursor apoptosis after acute anemia. Preliminary data indicate that miR-144/451 regulates iron uptake, survival, maturation, and mitochondrial energy metabolism during erythropoiesis through confirmed target mRNAs including Rab14, Myc, Ywhaz, and Cab39. We will investigate further the mechanisms through which miRs 144 and 451 control erythropoiesis at baseline, and during disease-related stresses including blood loss, iron deficiency, and unbalanced hemoglobin production (thalassemia). Our work should provide new insights into erythroid development and associated disorders including myeloproliferative syndromes and various anemias. Moreover, knowledge gained through our studies of erythropoiesis should be applicable to other biological processes where miR-451 is believed to function, including protection against myocardial stress, regulation of immune responses and as a tumor suppressor in numerous malignancies.