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A new class of cationic lipids that activate innate immune receptors (TLR4-CAT)
Date du début: 1 oct. 2013, Date de fin: 30 sept. 2015 PROJET  TERMINÉ 

Vaccine research has highlighted the need for effective adjuvant formulations that elicit strong, safe and protective cellular immune responses. Through recognition by Toll-like receptors (TLRs), adjuvants brings the immune system in a “state of emergency” required for an efficient vaccine formulation. Knowledge of TLR-mediated signalling, therefore, could lead to rational adjuvant design for vaccines. Bacterial lipopolysaccharides (LPS), major components of the outer membrane of Gram-negative bacteria, are recognized by TLR4. Most synthetic adjuvants designed so far are mimicking the LPS structure but their toxicity and the difficulties related to their synthesis and purification limit their use significantly. Hence, there is an urgent need to develop new efficient and safe adjuvants (not structurally related to LPS).SFMB laboratory in Brussels designed and synthesized a new cationic lipid, diC14-amidine, which activates TLR4-dependent cellular pathways, suggesting that this lipid is a good candidate for vaccine development. It is easy to synthesize and to modify in order to improve adjuvanticity.The main goal of this work is to study the interaction between this new class of immunomodulatory lipids and the components of the TLR-4 recognition system, to elucidate how this new class of ligands activate underlying signalling pathways, and to identify, at a molecular level, the characteristics required for an agonist activity. The long term goal is to design and synthesize, on a rational basis, new cationic lipids able to modulate the immune responses activated by TLR4 possibly leading to the development of new and safe adjuvants for vaccines.The multidisciplinarity nature of this application gives a real opportunity to achieve a major breakthrough in the field of adjuvants and immunomodulation. The unique expertise acquired by the applicant both in structural biology and immunology will undoubtedly improve her potential to reach professional maturity.