ESR01 – Emily Triffaux


ESR 1 Title: Increasing Treg function through pharmaceutical manipulation of FOXP3 activity
Research Objectives:
Description of work: UMCU made several novel observations concerning regulation of FOXP3 activity: (i) FOXP3 has a short half-life being ubiquitinated and rapidly degraded by the proteosome; (ii) FOXP3 is acetylated, protecting it from ubiquitin-mediated degradation, and (iii) FOXP3 activity is inhibited by Wnt-mediated TCF activation. The ESR will expand these observations to evaluate FOXP3’s role in the development of autoimmunity, and investigate whether manipulation of acetylation, ubiquitination or Wnt-signaling can modulate Treg function both in vitro and in vivo. He/she will focus on the regulation of the deubiquitinase (DUB) USP7, which we have shown can protect FOXP3 from proteosome-mediated degradation, and the SIRT1 deacetylase whose activity results in increased FOXP3 ubiquitination. He/she will investigate the regulation of SIRT1, USP7 and TCF activity in Treg by cytokines, and in particular whether these cytokines may play a role in inhibiting Treg functionality at sites of (auto)inflammation. These studies will include the use of SIRT1 and DUB inhibitors in mouse models of arthritis and colitis. Finally, using established activators and inhibitors of Wnt signaling he/she will investigate the possibility of modulating both Treg and Teff functionality in vivo. These studies will provide novel therapeutic routes for modulating immune tolerance.Personal Information Sheet ESR01 – Emily TriffauxPresentation ESR01 Emily Triffaux