Inhibierung der Makrophagenaktivierung durch TRIM47

Projekt: Forschungsförderung

Projektdetails

Abstract

Equally important to appropriate induction of immune signaling are the molecular mechanisms preventing
accidental induction during resting conditions and promoting return of the activated immune cells to their resting
state during resolution of infection. Disruptions in these homeostatic mechanisms can result in prolonged
immune activation and hyper-inflammatory diseases. Our knowledge on factors which dampen these responses
remains limited. The project proposed here focuses on determining how immune responses are curtailed in one
of the key leukocyte types in this context: macrophages.
We hypothesize that ubiquitination of activated proteins can be used as a means to negatively regulate the
immune system by altering their functional properties, or stability through lysosomal or proteasomal degradation.
In an E3 ligase screen for negative immune regulators we recently identified the tripartite motif protein 47
(TRIM47) E3 ligase as a novel putative inhibitor of the NF?B-dependent pro-inflammatory response.
Based on our preliminary data, I hypothesize that the putative ubiquitin E3 ligase TRIM47 is induced during
differentiation of precursor cells into macrophages, and that TRIM47 expression is important for maintaining these
newly derived cells in a non-inflammatory state by repressing NF?B-signaling, possibly in a Ub-dependent
manner.
Here, we will set out to investigate the contribution of TRIM47 to correct spatio-temporal repression of NF?B in
macrophagess, and consequently their pro-inflammatory response. In this context, I propose the following two
specific aims: Aim1) Determine the molecular mechanism by which TRIM47 represses NF?B-dependent cell
signaling, and Aim2) Determine how TRIM47 itself is regulated, and its importance for proper M? function.
For this project I request funding for two PhD students for three years: one for each of the aims. The success of
each aim is not dependent on the success of the other, yet both have great potential for synergy. For the
proposed project we will use primary macrophage cell model systems derived from mouse bone marrow and
human peripheral blood monocytes. State-of-the-art genetic manipulations using lentiviral vectors for the delivery
of genome engineering tools, ubiquitination assays, as well as proteomics approaches will be used to achieve
the set aims.
Together, the results from both aims will help us to understand in the long term how different molecules work
together at the cellular level to assure correct balance and activation in the immune response, and the
contribution to inflammatory disease when these immune-regulatory mechanisms are deregulated.
Academic abstract
3275 - Versteeg
Creation
KurztitelInhibierung der Makrophagenaktivierung durch TRIM47
StatusAbgeschlossen
Tatsächlicher Beginn/ -es Ende1/04/1730/04/20

Schlagwörter

  • ubiquitin
  • tripartite motif protein
  • TRIM
  • NFkB
  • macrophage