MIR155 · microRNA-155 expression control and function in innate immune inflammatory response
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2012-03-01 → 2016-02-29
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-CIG
Линиите свързват координатора с партньорите.
Накратко на български
МикроРНК-155 и протеинът KSRP регулират възпалителните реакции в макрофагите, които са защитни клетки на имунната система. Разбирането на тези механизми помага да се разбере как се контролират имунните функции и клетъчната смърт.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
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.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
MicroRNAs (miRNAs) are small non-coding RNAs which play critical roles in key biological processes, including immune response. miRNAs derive from transcripts (pri-miRNAs) which are processed by Drosha into intermediate hairpin precursors (pre-miRNAs). Pre-miRNAs are then processed by Dicer into mature forms of about 22 nucleotides. Mature miRNAs are loaded in the RNA-induced silencing complex (RISC) to mediate degradation and/or translation inhibition of specific target mRNAs. Many reports documented discrepancies in the levels of precursors and mature miRNAs indicating a wide potential for post-transcriptional control of miRNA expression. We recently discovered that the terminal loop structure of miRNA precursors plays a pivotal role as dock for co-activators of miRNA processing (e.g. KSRP) or co-repressors (e.g. Lin28), acting in a coordinated way to control miRNA biogenesis. Among the miRNAs post-transcriptionally regulated by KSRP we identified miR-155. miR-155 regulates both adaptive and innate immune responses. In macrophages, miR-155 maturation is induced upon lipopolysaccharide (LPS) stimulus. I hypothesize that a repressor complex is bound to pri-miR-155 in untreated macrophages to block the recruitment of KSRP and thus the maturation. LPS stimulus induces the dismissal of the repressor and the recruitment of the activator complex to pri-miR-155. Aims of my future work will be to identify in macrophages: i) the components of the regulatory complex(es) for miR-155 biogenesis; ii) the dynamics and the post-translational modifications that modulate the exchange between regulatory complexes; iii) novel miR-155 direct target mRNAs. This study will delineate the regulatory network that controls miR-155 maturation and function in macrophages allowing the design and the validation of tools capable of modulating it and, as a consequence, the magnitude of the innate immune inflammatory response.
Оригинален текст от CORDIS (на английски).
Участници
- INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · ParisКоординаторФранция
Връзки
Данни: CORDIS, © Европейски съюз