Investigate the function of miR-146a in myeloid development

描述（由申请人提供）：MicroRNAs （miRNA）代表一组进化上高度保守的小非编码RNA，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起着非常重要的作用。mirna表达水平的改变已被证明可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-146a （miR-146a）以nf - kb依赖的方式被脂多糖（LPS）和其他几种toll样受体（TLR）配体诱导。经诱导，miR-146a通过直接抑制TNF受体相关因子6 （TRAF6）和IL-1受体相关激酶1 （IRAK1）的表达，作为NF-kB通路的负调节因子。TNF受体相关因子6 （TRAF6）和IL-1受体相关激酶1 （IRAK1）是NF-kB信号通路的两种信号转导。因此，miR-146a被假设通过其对NF-kB的影响来调节炎症。最近，我们的实验室成功培育了一种靶向种系缺失miR-146a的敲除小鼠。miR-146a敲除小鼠的造血功能发生改变，脾脏和骨髓中的骨髓细胞扩增，表明miR-146a在调节正常造血发育方面具有重要功能。本研究的目的是了解miR-146a在正常造血发育中的功能，以及它在血液学起源疾病（如贫血、骨髓增生性疾病和骨髓增生异常综合征）中的潜在作用。本研究还将表征miR-146a与炎症的关系，并验证miR-146a是NF-kB信号传导的重要负调节因子的假设。在相关的生理和病理生理背景下，了解miRNA及其关键下游靶点的功能是miRNA领域的主要挑战。本研究项目为在敲除小鼠模型中研究miR-146a在造血发育中的作用提供了宝贵的机会。这将使我们对miR-146a发挥的发育功能以及炎症和造血之间有趣的相互作用有新的认识。上调miR-146a和/或下调其关键靶点可能为治疗慢性炎症和/或miR-146a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. PUBLIC HEALTH RELEVANCE: This research proposal is aimed to study the molecular mechanism that leads to chronic inflammation and abnormal blood cell development. Recent studies from mouse models and human clinical specimens have provided strong evidence that small nucleic acid molecules, called microRNAs, play important functions in our immune system and contribute to development of many diseases, including anemia, autoimmunity, myelodysplastic syndrome, and cancers. Studies from this proposal will tackle the questions of how microRNAs tip the balance between normal blood cell development and the diseased states.