Project 2

Structure-function relationships of extracellular S100 proteins, mediators of inflammation in human diseases

ESR2: Maria Demou

University of Montpellier, Laboratory of Pathogen Host Interactions (France)

Supervisor: Dr L. Yatime, co-supervisors: local: Dr G. Lutfalla, external: Prof V. Mulero (P9), non-academic: Axel Vater (P16)

Objectives: Critical mediators of inflammation during tumorigenesis, S100 proteins and their cell-surface receptors (RAGE, TLRs, Ig superfamily receptors) are important targets to down-tune systemic inflammation in anti-cancer therapies. Aims: 1) elucidate the structural basis for S100 proteins recognition by specific cell-surface PRRs using X-ray crystallography; 2) establish cancer relevant cellular and in vivo models to study their signalling pathways; 3) Cell and in vivo models to evaluate their role in inflammasomes and myeloid cell activation; 4) screen for new small molecule inhibitors of the S100: PRR interactions.

Expected Results: 1) Structure determination of S100 proteins and S100:PRR complexes using recombinant proteins and fragments produced in bacterial and mammalian expression systems; 2) Cellular and in vivo models to dissect S100-downstream signalling.

Secondments: Academic: P9 Murcia: V. Mulero, Month 23, 2 Months: inflammasomes activation. P7 CNRS: N. Peyrieras, Month 30, 1 Month: myeloid cell activation.