Investigate the function of miR-146a in myeloid development

描述（由申请人提供）：MicroRNA（miRNA）代表一组进化上高度保守的小的非编码RNA，其在信使RNA（mRNA）翻译和/或稳定性水平上抑制基因表达。这些只有19-22个核苷酸长的小RNA已被证明在哺乳动物免疫系统的发育和正常功能中发挥非常重要的作用。已经显示改变的miRNA表达水平导致造血发育失调和许多血液学起源的人类疾病，如贫血、自身免疫、骨髓增生异常综合征和癌症。 microRNA-146 a（miR-146 a）是由脂多糖（LPS）和其他几种Toll样受体（TLR）配体以NF-κ B依赖性方式诱导的。在诱导后，miR-146 a似乎通过直接抑制TNF受体相关因子6（TRAF 6）和IL-1受体相关激酶1（IRAK 1）（NF-κ B信号传导途径的两个信号转导子）的表达，作为NF-κ B信号传导途径的负调节因子发挥作用。因此，假设miR-146 a通过其对NF-kB的作用来调节炎症。最近，我们的实验室已经成功地产生了一个基因敲除小鼠与靶向生殖细胞删除miR-146 a。miR-146 a敲除小鼠的造血功能发生改变，脾和骨髓中的髓样细胞扩增，表明miR-146 a在调节正常造血发育中具有重要功能。 本研究的目的是了解miR-146 a在正常造血发育中的功能，以及其在血液学起源的疾病，如贫血，骨髓增生性疾病和骨髓增生异常综合征中的潜在参与。该研究还将表征miR-146 a与炎症之间的关系，并验证miR-146 a是NF-κ B信号传导的重要负调节因子的假设。了解miRNA及其关键下游靶标在相关生理和病理生理背景下的功能是miRNA领域的主要挑战。该研究项目为在基因敲除小鼠模型中研究miR-146 a在造血发育中的作用提供了宝贵的机会。这将使我们能够对miR-146 a发挥的发育功能以及炎症和造血之间有趣的相互作用获得新的见解。上调miR-146 a和/或下调其关键靶点可能为治疗慢性炎症和/或miR-146 a缺乏的血液病开辟新的治疗途径。

DESCRIPTION (provided by applicant): MicroRNAs (miRNA) represent a group of evolutionarily highly conserved small non-coding RNAs that repress gene expression at the level of messenger RNA (mRNA) translation and/or stability. These small RNAs of only 19-22 nucleotide-long have been shown to play a very important role in the development and the proper functioning of the mammalian immune system. Altered expression level of miRNAs has been shown to lead to dysregulated hematopoietic development and many human diseases of hematologic origin, such as anemia, autoimmunity, myelodysplastic syndrome, and cancers. MicroRNA-146a (miR-146a) is induced by lipopolysacharides (LPS) and several other Toll-like receptor (TLR) ligands in a NF-kB-dependent manner. And upon induction, miR-146a appears to function as a negative regulator of the NF-kB pathway by directly repressing the expressions of TNF receptor-associated factor 6 (TRAF6) and IL-1 receptor-associated kinase 1 (IRAK1), two of the signal transducers of the NF-kB signaling pathway. Thus, miR-146a is hypothesized to regulate inflammation through its effects on NF-kB. Recently, our lab has successfully generated a knockout mouse with targeted germline deletion of miR-146a. The miR-146a knockout mice developed an altered hematopoiesis with myeloid cell expansion in spleen and bone marrow, suggesting an important function of miR-146a in regulating normal hematopoietic development. The aims of this study are to understand the function of miR-146a in normal hematopoietic development as well as its potential involvement in diseases of hematologic origin, such anemia, myeloproliferative disease and myelodysplastic syndrome. The study will also characterize the relationship between miR-146a and inflammation, and test the hypothesis that miR-146a is an important negative regulator of the NF-kB signaling. To understand the function of a miRNA and its critical downstream targets in a relevant physiological and pathophysiological context is a major challenge in the miRNA field. This research project offers a valuable opportunity to study the role of miR-146a in hematopoietic development in a knockout mouse model. This will allow us to gain novel insights into the developmental functions played by miR-146a and the interesting interplay between inflammation and hematopoiesis. Up-regulating miR-146a and/or down-regulating its critical target(s) may open up a new therapeutic avenue for treating hematologic diseases with chronic inflammation and/or miR-146a-deficiency.