Retinopathy of prematurity (ROP) is the leading cause of blindness in children. This disease is characterized by inflammatory processes and abnormalities in vascular development of the retina. Preliminary results from our laboratories and published data show that specific lipids, such as plasmalogens and endocannabinoids, can regulate inflammatory processes as well as the development of blood vessels in different tissues. The EndoROP project brings together specialists in lipid metabolisms, inflammation and angiogenesis in the retina. It will characterize in details the place of plasmalogens and endocannabinoids in the regulation of retinal vascular development in ROP by: 1) understanding the plasmalogen-dependent molecular mechanisms by which endocannabinoids regulate retinal vascular development in physiologic conditions (Work-Package 1) ; 2) deciphering the cellular and molecular mechanisms involving plasmalogens and endocannabinoids in the pathologic conditions of ROP (Work-Package 2), and 3) identifying new therapeutic targets and develop new therapeutic approaches to prevent or to limit the retinal vascular abnormalities observed in ROP (Work-Package 3). Altogether, our project will document the molecular mechanisms by which plasmalogens regulate the endocannabinoid system in the retina and offer new therapeutic strategies to prevent ROP in premature infants.

Crohn’s disease and ulcerative colitis are severe inflammatory bowel diseases (IBD) that can end up in ulcer and fibrosis of the intestine. They are a worldwide health-care problem with a continuously increasing incidence. The available therapies are not curative, at best they provide temporary symptomatic relief but a large proportion of patients fail to respond or achieve remission in the short or the long term. Thus, there is a real need to develop new drugs less toxic and able to act both on the acute and chronic phases of the disease. IBD, whose etiology is still unknown, are characterized by an impaired and/or inappropriate pro-inflammatory response toward intestinal bacteria involving the recruitment of inflammatory macrophages, neutrophils and lymphocytes Th1/Th17, which induce the production of pro-inflammatory cytokines (i.e. TNFa, IL-23, IL-17) and an oxidative stress, both involved in the development of intestinal damage. Among different environmental factors, stress, via the secretion of catecholamines, has been shown to activate catecholaminergic receptors. a-adrenoceptors subtypes are described to boost inflammation while ß2-adrenergic signaling suppresses both innate and adaptive immunity. A third subtype, less studied, within this family is the ß-3 isoform of adrenergic receptor (ß3-AR). Knowledge concerning the relationship between ß3-AR and immunity is sparse. Nevertheless, we have recently demonstrated that the ß3-AR is expressed and functional in human macrophages. Its stimulation leads to anti-inflammatory and antioxidant responses and induces polarization toward a M2-like phenotype. Moreover, we have demonstrated that ß3-AR is also expressed on human lymphocytes and that its stimulation leads to cAMP production, a second messenger implicated in the suppressive activity of Tregs toward lymphocytes and dendritic cells. Lastly, our preliminary results in vivo show that a weekly exposure to a ß3-agonist results in protection against polyp formation in ApcMin mice, via an anti-inflammatory effect. Altogether, these results indicate that ß3-adrenoceptor stimulation could be of interest in inflammatory bowel diseases. However, ß3-agonists are highly lipophilic. Therefore, we intend to use our recently patented technology that uses lipoproteins (HDL-derivatives) as nanovectors both to solve solubility problems and to improve drug targeting to immune cells. Specific aims: 1) To dissect the role of ß3-AR on the host cell immune response using human in vitro, ex vivo explants and murine in vivo models, in order to bring a “proof of concept". 2) to develop a cost effective ß3-agonist formulation based on lipoprotein that could be given to patients in view to maintaining remission of inflammatory bowel diseases’ patients. To achieve these objectives, we propose a multidisciplinary approach associating expertise in human primary cell culture, human explants (organotypic cultures), in vivo studies in rodent IBD models, pharmacokinetics and pharmaco-imagery techniques. In terms of societal impact, we expect to develop a new formulation with a ß3-agonist that will be tested in clinical trials for its ability to maintain remission and prevent relapse in patients with IBD. The economic impact of this new formulation appears very promising considering the frequency of IBD worldwide and the need for more efficient and/or less toxic treatments. An originality of our approach worth to mention is that we want to re-educate immune cells instead of depleting them, like with recombinant antibodies therapy, thus potentially allowing the chronic use of the ß3-agonist formulation. B3ID is a translational research project that will provide a young researcher the opportunity to develop a research thematic and to constitute its own research group.

The environmental impact of packaging has become a major concern for the food industries, packaging, safety agencies but also consumers. This circular economy will force manufacturers to lighten packaging, recycle and/or reuse it, which implies having the same requirements in terms of health safety as for virgin materials. Indeed, materials in contact with foodstuffs (FCM) can transfer constituents to food by migration. In addition to substances of known origin, FCMs can also contain Non-Intentional Substances (NIS) (impurities, decomposition or reaction products, contaminants resulting from recycling, etc.), often of unknown and unpredictable origin. Most SNIs are neither identified nor quantified, and their toxicity has not been studied. This migration can pose a risk to human health, it must be measured and controlled. European Regulation 10/2011 on plastic materials also requires a risk assessment of SNIs, but to date there is no specific guideline or scientific consensus, making it difficult to assess and manage their risks. In addition, SNIs can be present in all packaging; recycled paper-cardboard, coatings, these can release more substances than their virgin equivalent. The evaluation of MCDA is currently only based on a study of the genotoxicity and the systemic effects of the starting substances, not taking into account endocrine disruption, nor the "cocktail effects" at low dose. Regarding SNI, it is recognized that the traditional approach based on the identification and quantification of all substances followed by their full toxicological characterization is not feasible (in terms of costs, time, quantity available, etc.). A relevant approach consists in using biotests in addition to analytical and physicochemical techniques on all of the substances which migrate. Biotests are already used with mixtures. However, they need to be better characterized in terms of sensitivity / specificity and robustness with complex extracts of MCDA. The first stage of this project will consist in selecting the most sensitive and specific biotests to identify a hazard (genotoxicity or endocrine disruptor) in packaging extracts by applying the “spiking” methodology, which consists of adding reference substances ( positive and negative) in order to verify the expected response. The extract will be split if the answer is a false negative or a false positive, in order to identify the responsible fraction containing the substances causing the unexpected effect. The second step will consist of testing the selected biotests using extracts from finished packaging that have been subjected to particularly SNI-generating processes (including recycled materials) to assess the risk. The innovative nature of this project is to use in parallel, chemical signatures of MCDA extracts and robust biotests in order to generate a database allowing decision-making and packaging security at different stages of their cycle of production life. In addition, it will generate data on the toxicity of new SNIs as well as potential "mixing" effects of the extract. Resulting from a multidisciplinary scientific approach, this project will help packaging manufacturers and their customers (processors, food industries) (1) to better guarantee the safety and conformity of their materials and (2) to encourage their innovation and / or their competitiveness, by offering them relevant and reliable scientific tools.

Brown adipose tissue plays a key role during cold exposure by generating heat, a process named thermogenesis. Thermogenesis is essential to maintain body temperature and brown fat activation improves the host’s metabolism. Various types of immune cells have been identified in brown adipose tissue and their contribution to thermogenesis has been suggested. Macrophages are the most abundant immune cells in brown fat. We recently identified several brown adipose tissue macrophage subsets co-existing within this tissue. The current proposal aims to investigate the functions and relative contribution of brown fat macrophage subsets to homeostatic tissue maintenance and during cold-induced thermogenesis and stress. Molecular biology (RNAseq, lipidomics) and cell biology (spectral cytometry, confocal microscopy) approaches combined to original mouse lines will be used for this project. This consortium gathers 4 research teams with complementary expertise in immunology, metabolism and lipidomics.

Hosts are usually infected by multiple parasites simultaneously. These parasites can be in conflict or benefit from the presence of each other. In this project, we wish to investigate the consequences of the infection by an intestinal nematode with immunosuppressive effects, on the infection dynamics of a Plasmodium species, both parasites infecting house mice. In the first work package, we wish to run a series of experiments to investigate the role of order and timing of infection on the infection dynamics and the cost paid by the host. In the second work package, we will implement an experimental evolution approach where the two parasites will be allowed to evolve under single infection conditions or under co-infection. In the third work package, we will adopt a modelling approach to investigate more broadly the conditions promoting the evolution of immunosuppressive strategies and the consequences on the co-infection dynamics.