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.
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.
|Pratama, Alvin; Srivastava, Monika; Williams, Naomi J et al. (2015) MicroRNA-146a regulates ICOS-ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres. Nat Commun 6:6436|
|Mehta, Arnav; Mann, Mati; Zhao, Jimmy L et al. (2015) The microRNA-212/132 cluster regulates B cell development by targeting Sox4. J Exp Med 212:1679-92|
|Zhao, Jimmy L; Baltimore, David (2015) Regulation of stress-induced hematopoiesis. Curr Opin Hematol 22:286-92|
|Mehta, Arnav; Zhao, Jimmy L; Sinha, Nikita et al. (2015) The MicroRNA-132 and MicroRNA-212 Cluster Regulates Hematopoietic Stem Cell Maintenance and Survival with Age by Buffering FOXO3 Expression. Immunity 42:1021-32|
|Zhao, Jimmy L; Ma, Chao; O'Connell, Ryan M et al. (2014) Conversion of danger signals into cytokine signals by hematopoietic stem and progenitor cells for regulation of stress-induced hematopoiesis. Cell Stem Cell 14:445-459|
|So, Alex Yick-Lun; Zhao, Jimmy L; Baltimore, David (2013) The Yin and Yang of microRNAs: leukemia and immunity. Immunol Rev 253:129-45|
|Zhao, Jimmy L; Rao, Dinesh S; O'Connell, Ryan M et al. (2013) MicroRNA-146a acts as a guardian of the quality and longevity of hematopoietic stem cells in mice. Elife 2:e00537|
|Cheng, Henry S; Sivachandran, Nirojini; Lau, Andrew et al. (2013) MicroRNA-146 represses endothelial activation by inhibiting pro-inflammatory pathways. EMBO Mol Med 5:1017-34|
|Figueiredo, Nuno; Chora, Angelo; Raquel, Helena et al. (2013) Anthracyclines induce DNA damage response-mediated protection against severe sepsis. Immunity 39:874-84|
|Yang, Lili; Boldin, Mark P; Yu, Yang et al. (2012) miR-146a controls the resolution of T cell responses in mice. J Exp Med 209:1655-70|
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