Project 5

Regulation of inflammatory responses by modulating the interactions between DAMPs (HMGB1) and its receptors (TLR4 and RAGE)

Host institute: Université Paris Cité, France (UP)
Supervisor: Dr Bruno Villoutreix (UP)
Co-supervisor: Dr Bob Kool (BP)

Objectives
1. To generate 3D models of HMGB1 and structure-based in silico screening.
2. To identify key interacting residues/domains between HMGB1 and TLR4/RAGE by use of computational and biophysical approaches and to build 3D structural model of HMGB1-TLR4/RAGE complex.
3. To identify and develop novel inhibitors (small compounds and peptides) to interrupt the interactions HMGB1-TLR4/RAGE complex. The obtained inhibitors will be tested in animal models in by the Doctoral Candidates of projects 1 and 10 (DC1 and DC10)
4. To develop imaging probes to use as diagnostic tools by utilization of identified new inhibitors. The probes will be applied as diagnostic tools and used to investigate translocation mechanism of HMGB1 during cell death in WP1&3 (DC1).

Expected Results
1. High quality 3D models of HMGB1 for structure-based virtual screening.
2. An epitope mapping of the interacting residues/domains between HMGB1 and its receptors which will be used to generate a 3D structural complex of HMGB1-TLR4/RAGE that can be utilized for in silico peptide design.
3. Novel inhibitors (small compounds and peptides) binding HMGB1 that can prevent the complex formation with TLR4/RAGE and consequently interfere the inflammatory response.
4. Innovative imaging probes targeting HMGB1 that can be used as diagnostic tools.

Secondments
- UMA (3 months)
- IIBB (3 months)
- BasicPharma (1 month)

Requirements
Qualifications: Master in Science (MSc) or equivalent, English B2 or above. The chosen applicant will be processed through the university application system and require the institution board approval prior to acceptance for doctoral studies.
Experience: Minimum of four years’ undergrad studies within the field of biomedicine, biology, bioinformatics, structural bioinformatics, or chemoinformatics. The applicant should have experience in different basic methodology within this large field of research.
Knowledge & skills: The applicant should have basic knowledge in ligand docking, protein structure analysis and good knowledge in Python programming and machine learning.
Abilities: In abundance to the aforementioned requirements, the applicant should possess the ability to successfully conduct literature studies i.e., retrieve, critically review, analyze, and summarize literature. The applicant should be fluent in English in both writing and speech and have good communication abilities.
Attitude and disposition: The Praetorian MSCA doctoral network requires abundant traveling and social settings. The applicant should be willing to present research orally and in writing, socialize and network at meetings within the consortium but also at major international conferences and at the home institution. The applicant is expected to voluntary contribute to the science community including engaging in scientific communities and PhD-communities in Paris.