Alpha-galactosylceramides (GalCer) are glycolipids extracted from a marin sponge which exhibited in vivo (animal and human) immunostimulating and immunoregulating properties. Their interaction with iNKT cells, which leads to the expansion and the activation of these cells, is responsible for these properties. The ceramide portion of GalCer molecules binds to the CD1d domain of Antigen Presenting Cells (APC) and the resulting complex is recognised by iNKT cells via an interaction between the galactose unit of GalCer and the TCR (T cell receptor). The iNKT cell is activated by this ternary CPA/GalCer/iNKT complex and thus produces large amounts of cytokines which have two different functions. The Th1 response (IFN-gamma, IL-2, ' cytokines) is pro-inflammatory and was used for anti-cancer and anti-infectious therapy whereas the Th2 response is immunoregulating and can be used for the treatment of systemic auto-immune diseases. The latter are indeed characterized by a depletion of iNKT cells and by a decline of their immunoregulating functions. The therapeutic potential of natural GalCer compounds is unfortunately eroded by their low in vivo stability (like most glycoconjugate molecules) and by their poorly selective immune response (almost no bias in the Th1/Th2 response). Our proposal thus concerns the synthesis of non-hydrolyzable GalCer surrogates designed for inducing a Th2-biased immune response in order to apply their immunoregulation properties to the treatment of systemic auto-immune diseases. In that purpose, CF2- and CFH-glycosidic analogues of GalCer (FluoroC-GalCer compounds), featuring shortened lipidic chains, will be synthesized (organic synthesis team, UMR 6014 Rouen). Their immune response will be evaluated using animal models of autoimmunity (immunology team, UPR 9021 Strasbourg) and a structural study (NMR and molecular modeling), aiming at the assessment of their mimicking properties, will be run (NMR/MolMod team, UMR 6014 Rouen). Our team has a long standing interest in the synthesis of fluorinated C-Glycosides, relying on the hypothesis that these surrogates, stable to chemical and enzymatic hydrolysis, are better sugar mimics than CH2-glycosides thanks to the effects of fluorine atoms. Our FluoroC-GalCer compounds will feature various lipidic chains lengths but short ones will be favoured. It has indeed been demonstrated that a Th2-biased response (immunoregulation) was generally obtained with short ceramide chains. A methodology recently developed by our group, based on the addition of electrophilic fluorinated radicals to glycals, will allow us to prepare alpha-CF2-galactose and alpha-CFH-galactose synthons which will be further functionalized to set up the ceramide chains. The synthesized FluoroC-GalCer compounds will afterwards be subjected to different biological tests in order to assess their immunoregulation properties and their therapeutic potential for the treatment of auto-immune diseases such as systemic lupus erythematosus (SLE). A first ex vivo test with healthy mice will allow us to measure the iNKT cells proliferation and the cytokine production (Th2/Th1 balance), followed by an in vivo experiment (lupus mice) which will assess the iNKT cell expansion and the evolution of the disease. Finally, an ex vivo test, using human cells from SLE patients, will allow us to evaluate the recognition of our molecules by human iNKT cells. A structural study of two FluoroC-GalCer compounds (CF2 and CFH with short lipidic chains) will also be completed (NMR/MolMod team, UMR 6014 Rouen). A conformational analysis, using molecular modeling and 2D-NMR spectroscopy, will allow us to determine if the conformational behaviour of the FluoroC-GalCers is close enough to their natural counterparts to consider them as appropriate surrogates. Finally, a simulation study of the interactions between FluoroC-GalCers and CD1d (docking) using molecular modeling will provide data regarding the binding abilities of our compounds. Both studies (conformational analysis and docking) will provide information that should be helpful to rationalize the immune response induced by the FluoroC-GalCer compounds. Moreover, the combination of these structural data with the results obtained by the Immunology team could help us to design in the future a second generation of ligands, more performing than these first analogues.

The increased demand from pharmaceutical industry for single-enantiomer heterocylic compounds, accessible by environmentally benign and economically reliable asymmetric catalytic methodologies, have placed the use of organocatalysts as major tools in that field. This project aims to construct a novel research group concerned by the achievement of organocatalytic biotarget-oriented stereoselective synthesis of libraries chiral pyrazoline derivatives, by means of the concept of masked hydrazine as building blocks. Our collaborative-program with biologists is driven by the rapid elaboration and evaluation of novel ligands for cannabinoid (CB) receptors based on pyrazoline scaffolds or congeners thereof. Such heterocycles are emerging as potent CB1 inverse agonist connected with extreme food intake and addiction problems (cigarette, drugs…). Obesity is recognized as a serious health concerns by the World Health Organization. Original dihydropyridine pyrazolines-derived prodrugs will be evaluated to deliver these ligands into the Central Nervous System through the lipophilic Blood Brain Barrier, based on Bodor's vectorisation concept. The selective modulation CB2 receptors in immune cells will be also studied to evolve into modulation of inflammations, allergies, etc, significant threat of the future.

The aim of this project is the elaboration of a new biosourced polyamide-based UV powder coating for heat sensitive substrates. Indeed, polyamides are totally absent from this application field whereas they exhibit excellent mechanical properties and solvent resistance. This powder coating will be constituted of low melting point polyamides (< 120°C) made of monomers from vegetable oils. The low mechanical properties which will result from the low crystallinity of these polyamides will be compensated for an additional photocrosslinking step during its implementation. Therefore, polyamides will be elaborated from modified fatty acids coming from vegetable oils. Some original unsaturated monomers will be synthesized within this framework. They will potentially have a high impact in the polymer world. The powder composition and the coating elaboration conditions will be optimized by the mechanistic study of the photochemical reaction and the characterization of the physico-chemical properties of the ultimate materials. The team constituted within the framework of this project will associate young researchers who have expertises in polymer field (PBS, UMR CNRS 6270 – INSA of Rouen) and structural analysis of chemical compounds by mass spectrometry (COBRA, UMR CNRS 6014 – University of Rouen). This association will permit to precisely characterize the new synthesized monomers and polymers and to define the nature of the functional groups which will intervene in the photocrosslinking reaction and so, to determine the best composition of the powder coating.

The goal of intrusion detection is to monitor the activity of an information system for the occurrence of malicious activities intended to violate the security policy governing the confidentiality, integrity and availability of services and data. In order to maintain a complete picture of the security, several intrusion detection systems need to be distributed throughout the monitored network. However, since these systems are susceptible of generating a large amount of inaccurate and redundant observations, an additional layer is necessary to reason about these observations. This is the purpose of alarm correlation. The PLACID project addresses two major challenges in alarm correlation, namely the problem of cooperation between heterogeneous sensors and the uncertainty of observations. Having a common logic is a prerequisite for any correlation approach to reason about security observations. Indeed, most correlation schemes proposed so far need information about attacks and the context in which they occur. Besides, there is currently no formal language that fully allows to describe these information, even if some languages provide a formal description of preconditions and consequences of actions. Therefore, the first objective of the project is to propose formal logics, with a special focus on a description logics, that federate the information required for intrusion detection components to cooperate, to reason about events and to model admnistrator's preferences. These logics would provide a strong theoretical foundation and a methodological tool for any alarm correlation techniques. Uncertainty of alerts and observations is one of the major challenges in intrusion detection. Indeed, a majority of the numerous alerts triggered by intrusion detection system turn out to be false alarms. We propose to study the use of Bayesian networks, which are a well known paradigm for reasoning under uncertainty, in order to reduce attack's scenarios, to evaluate a success of a given attack and to enhance the diagnosis of alerts by taking into account evidence information modeled in the aforementioned description logic.