The worldwide prevalence of Gestational Diabetes Mellitus (GDM) has increased steadily over the last decade, affecting up to 10.8 % of the pregnancies in France, mainly due to the rising proportion of women with pre-pregnancy overweight, sedentary lifestyle and advanced maternal age at birth. GDM fuels the type 2 diabetes (T2D) epidemic in the next generation. Whether nutritional interventions during critical time windows in early life, such as breastfeeding could mitigate this risk remains to be explored. Indeed, despite emerging evidence of the infant-health benefit of breastfeeding in GDM, there is still a paucity of data concerning GDM-breast milk (BM) composition in regard with consensual key regulators of energy homeostasis and insulin sensitivity. In original studies, GDM-MILK consortium reported adaptations of BM composition in link with maternal diet or physiological status in human cohorts and in a cross-fostering rodent model of programming. Interestingly, in a pilot study conducted on GDM mothers, using comprehensive human BM (HBM) metabolomics/lipidomics analyses, we evidenced a specific GDM-HBM signature. Based on these preliminary data, GDM-MILK plans to (i) achieve the identification and validation of BM bioactive compounds associated with maternal glycaemia in existing human cohorts and integrate compositional and clinical data, (ii) validate the HBM bioactive components in a pre-clinical rodent model of GDM and explore the mechanisms of adaptations of key maternal organs (pancreas-placenta-mammary gland) impacting GDM-milk composition, and (iii) in vivo using cross-fostering, evaluate the functional impact of a cocktail of milk components previously selected by in vitro studies, on the sensitivity/secretion of insulin in the male and female offspring. This project will provide a major breakthrough in the understanding of lactation period as a sustainable intervention that may curb the T2D pandemic in the next generations and also yield the scientific basis for nutritional recommendations for mothers with GDM and their infants. Therefore, GDM-MILK perfectly fits the research axis Translational Health Research.

Leishmaniases are a complex of tropical and sub-tropical diseases provoked by Leishmania protozoan parasites transmitted by the sandfly vector and presenting different clinical expressions. In 2018, about 12 million Humans are affected by leishmaniases but global climate warming and population movements increase spreading of the diseases. In South-European countries, L. infantum affects mainly 2.5 million dogs and sometimes humans. New canine cases are estimated at 40,000 a year in South of France whereas several hundreds of human cases occur annually in Southern Europe, mainly in children and immune-compromised patients. The anti-leishmanial chemotherapy is expensive, aspecific therefore toxic, and drug resistance is usual or at risk, mainly to antimonials, the most classical drugs, and recently to miltefosine and amphotericin B. Despite the recent launching of CaniLeish, the first vaccine against canine leishmaniasis, new treatments are urgently needed because the vaccinal protection of dogs is expected to only reduce parasite loads in vivo and no vaccine is presently available for Human use. As a consequence, leishmaniasis is still poorly managed both in dogs and Humans. Parasites such as Leishmania successfully strive in host cells because they divert the intracellular trafficking machinery to maintain their parasitophorous vacuole in which they proliferate. Inhibitors of key elements of this diverted machinery should handicap the parasite survival. We have identified inhibitors of the plant toxin ricin by molecular screening (Stechmann et al., Cell 2010). One molecule, called ABMA, efficiently protects cells against various toxins and pathogens including viruses, intracellular bacteria and parasite Leishmania infantum (Wu et al., Scientific reports 2017). As the mechanism of action of ABMA is restricted to host-endosomal compartments, it reduces cell infection by pathogens that depend on this pathway to invade cells. Thus, acting on the host cells and not on the pathogens, the molecule acts as cell protectant. We screened over a hundred analogues of ABMA against L. infantum axenic and intra-macrophage amastigote forms of the parasite and observed various anti-parasitic activities. Lead compounds were selected based on selective activity against intramacrophage amastigote forms as well as favorable physicochemical properties. In vivo proof of concept was confirmed with an ABMA derivative in a mouse model of infection by intraperitoneal route reducing liver and spleen parasitic burden to 83% after a 5-day treatment. Further analogue selection on drugability criteria led us to identify one potential drug candidate with one back-up analogue that have physicochemical properties compatible with production of an easy to produce, low cost, standard pill for oral administration for the treatment of leishmaniasis. The ultimate goal of the project is to develop of a new class of oral anti-leishmanial drug, targeting components of the host's intracellular machinery instead of targeting the parasites therefore reducing the risk of drug resistance acquisition by the parasites. Our objectives are to raise lead compounds development to TRL4: a drug candidate and its backup ready for regulatory safety studies and clinical evaluation in infected leishmaniasis dog patients. To this end, we shall achieve: (1) Scale-up synthesis in a scheme compatible with pharmaceutical production; (2) In depth physicochemical characterization of best crystal forms ensuring stability, solubility after oral administration and formulation; (3) Radiolabeling and biodistribution of the parent drug and metabolites in mice; (4) Determination dose and duration of treatment, acute and chronic toxicity evaluation; (5) Pharmacokinetics, metabolites and pre-regulatory tolerance in dogs; (5) Full identification, synthesis and antiparasite activity evaluation of main metabolites identified in dogs; (6) Deciphering mechanism of protection of cells from parasite growth.

Bioorthogonal chemistry provides the possibility to achieve unnatural chemical reactions in living systems without interfering with native bioprocesses. Along the past years, several ligation and click-to-release reactions have been developed enabling to understand or manipulate biological processes through the formation or the breaking of chemical bounds in a stringently controlled fashion. However, the portfolio of reactions that can be undertaken in living systems is yet very small, especially when compared to the wide diversity of chemical transformations that can be conducted in organic solvents. In the NanoChem project, we propose to introduce a new paradigm in the field of bioorthogonal chemistry based on stimuli-responsive bioorthogonal nanoreactors, designed for the ‘on-demand’ synthesis of molecules in living systems. These nanoreactors will be programmed for allowing various chemical transformations in living systems such as coupling reactions, cyclizations, polymerizations, rearrangements and autocatalytic processes. In contrast to previous strategies, the NanoChem technology will allow the formation of chemical bonds that are present in natural products (e.g. urea, amide) without interfering with surrounding biologics. Since such chemistry will take place in a confined space, reaction rates should be considerably accelerated thereby limiting issues associated to the high dilution conditions meet in living systems. Furthermore, the NanoChem technology will offer the possibility to trigger autocatalysis in biological media, leading to signal amplification processes in which one bioorthogonal event will conduct to the activation of multiple bioactive compounds. Thus, this original project in the field of chemistry could lead to potential applications in the domain of human health.

Bipolar disorder is a severe chronic psychiatric disorder affecting 1% of the population. Lithium is its gold standard treatment. Human MRI and preclinical studies suggest that it may increase neurogenesis, neuroprotection, myelination and modulate synaptic plasticity and neuroinflammation. However, many aspects of its mode of action remain unknown: which cellular effects are associated with the “MRI effects” of lithium in patients? Are its therapeutic cellular effects region specific or brain wide? We will conduct 2 parallel studies (in rats and humans) using similar (longitudinal) designs and methods ([11C]-UCB-J PET and MRI) plus histology and immunochemistry in the rats. We will assess synaptic plasticity, myelination, oligodendrocytes, neurogenesis and neuroinflammatory aspects associated with lithium in the same study. We will thus be able to draw inferences and inter species correspondences between PET/MR findings and immunohistological findings

The Electrophylle project seeks to characterize a fundamental process involved in the initial transformation of light energy in the reaction center of Photosystem II that initiates photosynthesis in plants and algae. Electrophylle will create a synergy around a new gas phase experimental method applied to chlorophyll systems, a condensed phase approach and their theoretical modeling. Photosystem II (PSII) plays a central role during photosynthesis: indeed, solar energy collected by the antennae is transferred to PSII where the initial charge separation takes place, leading after subsequent steps to a negative charge production and water splitting into dioxygen+ protons. This charge separation is the initial and limiting step to the production of energy and dioxygen, the sources of life. Its quantum efficiency is close to unity and remains unexplained unless one accepts an hypothesis involving a resonant effect and is produced by natural evolutive adaptation. Indeed, the core of the PSII reaction center consists of a set of 12 chlorophyll-related molecules undergoing excitonic coupling, which can be reduced to a working ensemble of only 4 molecules. 2D time-domain spectroscopy measurements indicate the crucial influence in the efficiency of the charge separation mechanism, of resonances between chlorophyll vibration frequencies and the energy gaps separating neutral from ionic pairs. The resulting model reproduces the initial charge separation dynamics in this reaction center based however on fragmentary spectroscopic data. The electronic and vibrational structure of the elements in the core of the PSII reaction center, the chlorophylls, their excitonic pairs are insufficiently known to validate the essential hypothesis of a vibration energy gap resonance that will establish a new model. This can only be achieved by measurements in the gas phase or cryogenic solutions or as in the Electrophylle project, by a combination of both with quantum chemistry calculations. We propose to determine by resonant electron photodetachment spectroscopy, the vibrational and electronic structure of neutral chlorophyll and chlorophyll dimers cooled at 10K and electron tagged. Gas phase spectroscopy of biomolecules has the unique advantage of allowing access to the structure of biomolecules in the absence of medium interactions and being directly comparable to the results of quantum computations. On the other hand, we will achieve microsolvation of chlorophylls by single molecular bonds to bring them into dimers akin to those of the reaction center. This step is essential since it allows tuning their electronic levels into resonance with chlorophyll vibrations that drive charge separation with maximum efficiency. These gas phase measurements will be combined with fluorescence line narrowing (FLN) spectroscopy that addresses the interacting dimers in the protein environment. This will give access to a complete picture of the interaction landscape in chlorophyll dimers in several conditions, from free to assembled into special pairs. Specific quantum calculations will characterize the electronic and vibrational structure of these systems. This will yield energy level positions for chlorophylls and pairs in ground and first electronically excited states, together with a landscape of the interactions within chlorophyll pairs between neutral and ionic states. This project is designed to characterize a fundamental process related to energy transformation –photosynthesis- by a synergy between a new experimental method as applied to a complex system, the reaction center of Photosytem II, theoretical modelling and condensed phase spectroscopy. The precise modeling and understanding of such a fundamental process could help boosting the efficiency of artificial molecular photocatalysts, the electronic properties of which could be tuned to improve their ability of performing ultrafast (10-12 s) charge separation with high quantum yield.