CADET · Post-transcriptional Control of the Aire-Driven expression of self-antigens in the Thymus
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2011-08-01 → 2015-07-31
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-CIG
Линиите свързват координатора с партньорите.
Накратко на български
Механизмите в тимуса контролират кои собствени протеини на тялото се показват на maturing лимфоцитите чрез малки молекули, наречени miRNA. Разбирането на този процес помага за търсенето на нови терапевтични подходи за борба с автоимунните заболявания.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Post-transcriptional Control of the Aire-Driven expression of self-antigens in the Thymus
The main function of the immune system is to fight against infections in recognizing foreign constituents. But the immune system also needs to tolerate our body’s own proteins (the self-antigens or auto-antigens) through a mechanism called immunological tolerance. The completion of this project provides decisive insights into the understanding of how our self-constituents are presented to the maturing lymphocytes in the thymus, with the goal to educate them to the self in order to avoid the occurrence of autoimmune diseases. The first main finding that this project revealed is an important additional layer of control of self-antigen expression in the thymus, occurring at the post-transcriptional level. The project revealed that the post-transcriptional regulation in the cells that express the self in the thymus (the MECs), is mediated by small RNAs called miRNAs that accumulate to set a cellular repressive milieu leading to downregulation of gene expression by the specific degradation of mRNAs. This project revealed that the AIRE protein or (Autoimmune Regulator) induces a wide array or self-antigens whose mRNAs have the ability to escape this post-transcriptional repression, resulting in their higher relative expression and enhanced presentation to the mature lymphocytes. The involvement of miRNAs in the control of self-antigen expression in the thymus suggest potential new therapeutic approaches to fight against autoimmune diseases, notably a MEC-specific delivery of short hairpin RNAs targeting Drosha and whose knockdown would impair the entire RNAi pathway. This would result in the enhancement of self-antigen expression and presentation to maturing lymphocytes in the thymus. The other main finding that this project revealed is the identification of CLP1, an RNA-binding factor, that plays a key role in this mechanism and that interacts with AIRE. This research showed that CLP1 is involved in the miRNA-mediated post-transcriptional repression, resulting in the degradation of transcripts with long RNA sequences susceptible to be recognized by miRNAs and thereby in a higher proportion of short transcripts that can be preferentially presented to the immunological cells. The identification of CLP1 could also provide a new therapeutic target to potentially re-establish immune tolerance in deficient individuals. Altogether these results should provide invaluable insights into the mode of action of AIRE and into the fine understanding of immunological tolerance in the thymus. In addition to be of considerable interest into the understanding of promiscuous expression, the identification of CLP1 may also help to understand the escape of the miRNA-mediated repression in other systems, like in cancer cells. Indeed, since CLP1 like other RNA-binding factors recruited by AIRE are general effectors, it will be worthwhile testing their impact on oncogene expression and malignant transformation. As this is an epigenic mechanism, it could theoretically be reversed, perhaps providing a new strategy for cancer treatment using specific inhibitors of the post-transcriptional repression.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Immune tolerance is key to the maintenance of the integrity of organisms against foreign invaders with respect to self-constituents. Deregulation of this mechanism promotes the occurrence of life-threatening autoimmune diseases that affect 5-10% of the general population. Previously, the transcriptional activator (Aire) was shown to play a key role in immune tolerance. Indeed, Aire induces medullary epithelial cells in the thymus (MECs) to synthesize and present a large repertoire of peripheral self-antigens (a “self-shadow”), leading to the clonal deletion of self-reactive maturing T cells and thereby protecting against autoimmune manifestations. In addition to activating transcription, preliminary results indicate that Aire induces 3’UTR shortening of its sensitive transcripts in MECs, and that these cells show an accumulation of miRNAs. The goal of our project is to describe a post-transcriptional control of the Aire-driven expression in the thymus that leads to higher levels of Aire-dependent self-antigens, and to identify key molecular players involved in this mechanism. We first propose to confirm that Aire-induced transcripts have shorter 3’UTR ends by mRNA high-throughput sequencing in primary MECs, and that these transcripts escape a miRNA-mediated post-transcriptional repression in a MEC cell line. We will also seek factors involved in Aire-triggered 3’UTR shortening by performing a lentivirus-based RNAi screen of a set of RNA-binding proteins in an in vitro model that we will set up. Finally we will validate some of the best candidates in vivo by generating knock-down mice using a high-speed lentigenic approach based on oocytes infection with lentiviruses delivering targeting short-hairpin RNAs. Altogether the expected results should uncover an important layer of control of self-antigen expression in the thymus mediating immune tolerance, and provide new potential targets for therapeutic intervention in autoimmune diseases.
Оригинален текст от CORDIS (на английски).
Участници
- INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · ParisКоординаторФранция
Връзки
Данни: CORDIS, © Европейски съюз