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

描述（由申请人提供）：我们寻求发现新的、医学上相关的控制红细胞形成（红细胞生成）的机制。最近发现的小的非编码rna，称为microRNAs (miRs)，深刻地影响几乎所有组织的正常发育和应激反应。MiRs通过抑制通过沃森-克里克碱基配对识别的特定靶mrna的翻译和稳定性来抑制蛋白质合成。本研究探讨了mirs144和451的作用，这两个基因编码在单个基因位点上，在红细胞生成过程中被强烈诱导。在斑马鱼和小鼠中，miR-451的缺失会损害红细胞生成，使成熟红细胞对氧化应激的破坏敏感，并在急性贫血后诱导红细胞前体凋亡。初步数据表明，miR-144/451通过Rab14、Myc、Ywhaz和Cab39等已确认的靶mrna调控红细胞生成过程中的铁摄取、存活、成熟和线粒体能量代谢。我们将进一步研究mirs144和451在基线和疾病相关应激（包括失血、缺铁和血红蛋白生成不平衡（地中海贫血））时控制红细胞生成的机制。我们的工作将为红细胞发育和相关疾病，包括骨髓增生性综合征和各种贫血提供新的见解。此外，通过我们的红细胞生成研究获得的知识应该适用于miR-451被认为具有功能的其他生物过程，包括保护心肌应激，调节免疫反应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.