Objetivo Autoimmunity is caused by chronic inflammation mediated by T- and B-lymphocytes. Thus far, treatment of autoimmunity consists of general immune suppressants, causing unwarranted side effects, without curing disease. Therefore, the need for a specific treatment targeting the cause of disease is growing. In this fellowship will focus on elucidating how SNPs (single nucleotide polymorphisms) in RasGRP1 play a role in aberrant lymphocyte activity in patients with autoimmunity. RasGRP1 is critical in the activation of Ras, resulting in lymphocyte activation. Preliminary data show that a point mutation in Rasgrp1, Rasgrp1Anaef, results in autoimmunity in mice, characterized by anti-nuclear antibodies and activated CD4+ T cells. Moreover, Rasgrp1Anaef/wildtype heterozygote mice show a similar phenotype, arguing that one wildtype allele cannot compensate for the Rasgrp1Anaef allele. We have established that hypomorphic Rasgrp1 variants can exert a dominant negative effect, which relies on coiled-coil mediated dimerization with wildtype Rasgrp1. This new concept of RasGRP1 dimerization, suggests that monoallelic, non-synonymous RasGRP1 variants may affect the activity of a RasGRP1 dimer in patients.In the proposed fellowship, I will: (1) Model non-synonymous SNPs in patients to our structure of RasGRP1 and test the functional effect, (2) Establish how dimerization affects RasGRP1 function, and (3) Establish if RasGRP1 signaling is aberrant in lymphocytes of patients.This will help us understand how autoimmunity comes about, and will provide new potential strategies for development of more specific therapies. I anticipate that these RasGRP1-centric studies will function as a paradigm for future studies on dysregulated signaling pathways in autoimmune T cells. This fellowship will put me in an excellent position to start my independent research in Europe, introducing functional research of SNPs in key lymphocyte signaling molecules to the field of (pediatric) rheumatology. Ámbito científico medical and health sciencesclinical medicinerheumatologymedical and health sciencesbasic medicineimmunologyautoimmune diseasesnatural sciencesbiological sciencesgeneticsmutationnatural sciencesmathematicspure mathematicsmathematical analysisfunctional analysisnatural sciencesbiological sciencesgeneticsnucleotides Programa(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Tema(s) FP7-PEOPLE-2012-IOF - Marie Curie Action: "International Outgoing Fellowships for Career Development" Convocatoria de propuestas FP7-PEOPLE-2012-IOF Consulte otros proyectos de esta convocatoria Régimen de financiación MC-IOF - International Outgoing Fellowships (IOF) Coordinador UNIVERSITAIR MEDISCH CENTRUM UTRECHT Aportación de la UE € 259 745,10 Dirección HEIDELBERGLAAN 100 3584 CX Utrecht Países Bajos Ver en el mapa Región West-Nederland Utrecht Utrecht Tipo de actividad Higher or Secondary Education Establishments Contacto administrativo Berent Prakken (Prof.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos
