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microRNA-155 expression control and function in innate immune inflammatory response

Final Report Summary - MIR155 (microRNA-155 expression control and function in innate immune inflammatory response)

The discovery of regulatory small RNAs represents a major breakthrough in recent biomedical history. Although, three major classes of small RNAs have been identified, namely the microRNA (miRNA), the small-interfering RNA (siRNA), and the piwi-interacting RNA (piRNA), many other regulatory small RNAs have been identified, including small RNAs coming from Alus, tRNAs, snoRNAs (Hu, Q. et al. Nat Struct Mol Biol, 2012. 19: p.1168; Miyoshi, K. et al. Mol Genet Genomics, 2010, 284: p. 95). They differ in their biogenesis, length, and tissue distribution [Ghildiyal, M. and P.D. Zamore. Nat Rev Genet, 2009. 10(2): p. 94; Kim, V.N. J. Han, and M.C. Siomi. Nat Rev Mol Cell Biol, 2009. 10(2): p. 126]. miRNAs are ubiquitously expressed and control a wide range of cellular activities, including development, immune function, and cell death. In 2009, Dr. Michele Trabucchi found that KSRP in addition to serve as an essential decay-promoting factor for many inherently labile mRNAs is also an unanticipated and required component of the two multiprotein complexes containing the ribonucleases Drosha and Dicer, respectively [Trabucchi, M. et al. Nature, 2009. 459: p. 1010]. KSRP promotes the the maturation of a subset of miRNAs, including miR-155 in activated macrophages. Within the Marie Curie Career Integration Grant (MC-CIG) program, the fellow used a proteomic approach to identify novel KSRP-containing complex(es) associated to miRNA pathway in macrophages. In addition to the already known KSRP-associated proteins, he found novel proteins. The team headed by the fellow also generated a miR-155 knockout mouse line in FVB moue strain to investigate by HITS-CLIP the regulation of the direct miR-155-target mRNAs the impact of the KSRP-partners on the activity of miR-155 in macrophages and, therefore, the overall impact of the inflammatory response. The fellow foresees to nail down soon with a publication novel mechanism(s) of KSRP/miRNA-mediated by gene expression programs in activated macrophages. Overall, this study aims at defining the molecular mechanisms underlying miR-155 expression and functional regulation during innate immune and inflammatory responses, by using new up-to-date technological tools, such as deep sequencing analysis.
Since Dr. Trabucchi started the Marie Curie Career Integration Grant program, he has been appointed as tenured researcher (equivalent to an Assistant Professor position) within the INSERM, a French Research Institution. He made substantial progression in his career goals, by opening his own independent laboratory (hosting 2 tenure scientists, 2 post-doctoral fellows, 5 graduate students, 1 master student, and 1 technician) obtaining 8 French National grants, publishing 4 original research papers, including 2 as last and corresponding author (Plos Genetics 2012,8(7): e1002823 and BMC Medicine 2015,13(1):259), 2 review papers as corresponding author, and 1 European patent (n° EP 13 306 439.4) which is currently in maturation phase.