Projektbeschreibung
Posttranslationale Modifikationen und T-Zell-Funktion
T-Lymphozyten sind die Hauptakteure des Immunsystems, und ihre bemerkenswerte Potenz und Spezifität machen sie zu einem wertvollen Ansatzpunkt im Bereich der Immuntherapie. Daher ist es von grundlegender Bedeutung, die Biologie der T-Zellen und die Faktoren zu erforschen, die ihre Aktivierung beeinflussen. Das Team des vom Europäischen Forschungsrat finanzierten Projekts RELYUBL konzentriert sich auf die Ubiquitinierung, eine posttranslationale Modifikation, von der bekannt ist, dass sie eine Rolle bei der adaptiven Immunität spielt, wobei es bei immunologischen Erkrankungen zu einer Störung von Komponenten des Ubiquitinierungssystems kommt. Das Ziel von RELYUBL ist es, die Ubiquitinierung in T-Zellen zu untersuchen und die regulatorische Rolle von Ubiquitin bei Immunreaktionen aufzudecken. Die Ergebnisse des Projekts haben das Potenzial, Lymphozyten-vermittelte Therapien zu verbessern.
Ziel
T lymphocytes are key cells of the adaptive immune system that protect us against pathogens and malignant cells. T cell activation and differentiation are tightly controlled processes and deregulation can result in lymphomas, autoimmunity and inflammation. Hence, the biochemical events regulating lymphocyte biology have long been a topic of intense research, which has been focussed predominantly on protein phosphorylation. I hypothesize that there are crucial roles undiscovered in T cells for other posttranslational modifications (PTMs) such as ubiquitin (Ub) and Ub-like proteins (UBLs). The importance of ubiquitylation in adaptive immunity is implied by the severe immunological disorders observed when components of the Ub system are disrupted in lymphocytes. Genetic approaches in mice give a limited understanding about the roles of these modifiers and do not reveal the full extent to which Ub and UBLs regulate lymphocyte biology. Deterred by the complexity of the Ub system, the field has not yet tackled the daunting challenge of systematically investigating these modifiers in vivo. The goal of this proposal is to define how T cell function and immune responses are regulated by Ub and UBL signalling networks. To pioneer substantial progress in this area, we will develop new methods to identify and characterize currently unknown recognition modules for the different modifications. We will elucidate the Ub and UBL modified proteome in lymphocytes and characterize dynamic changes of these PTMs during T cell activation. By focussing on enzymes that remove the modifications we will discover how these PTMs are regulated and define Ub and UBL-dependent signalling nodes. Each phase of the work will deliver fundamentally novel mechanistic insights into these PTMs while rewriting current concepts of signalling in lymphocytes. Ultimately, this work will inform therapies seeking to target lymphocyte activity in disease.
Wissenschaftliches Gebiet
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- natural sciencesbiological sciencescell biology
- medical and health sciencesbasic medicineimmunologyimmunotherapy
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
- natural sciencesbiological sciencesmolecular biologystructural biology
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-STG - Starting GrantGastgebende Einrichtung
DD1 4HN Dundee
Vereinigtes Königreich