While sex differences in susceptibility to infections, allergy or autoimmune diseases are well documented, the underlying biological mechanisms are not sufficiently studied. At the onset of adolescence, asthma becomes less prevalent in men than in women, suggesting a protective role of male sex hormones. Based on the crucial role of group 2 innate lymphoid cells (ILC2) in the induction of airway inflammation, we made the hypothesis that ILC2 could be influenced by sex hormones. We could demonstrate for the first time that androgen, via the activation of its receptor AR (androgen receptor) acts as a powerful negative regulator of ILC2 development and expansion. In this proposal, we will determine the molecular mechanisms behind these observations. Our project will help to characterize new molecular mechanisms regulating ILC2 and will lead to a better understanding of the mechanisms responsible for sex-differences in immune responses.

Faced with an ageing population and the multiplication of targeted therapies, precision medicine requires increasingly sophisticated diagnostic and patient management tools. Due to its ability to characterize physiopathological mechanisms, positron emission tomography (PET) imaging represents an obvious tool for the future in order to move towards this personalized medicine for patients suffering from neurological diseases and cancers. In this context, ToNIC and the company Zionexa propose to develop innovative PET imaging radiotracers, drawing on their expertise in radiochemistry and radiopharmacy. On the strength of the past collaborations of these two partners, the IMoToul project will benefit from an essential asset for the successful completion of its projects through two strands of development of radiopharmaceutical drugs (MRP), in neurology and oncology. The IMoToul project will cover two key elements of cerebral physiopathology: 1) the key role of glutamate receptors (e.g. in Alzheimer's disease, Tourette's syndrome) and 2) the neuroinflammation mechanisms that accompany many neuropathological processes and which also occur in cancer patients. Moreover, today Fluor 18 (F18) remains the radioelement of choice for the development of MRP, however the advent of the development of small molecules (peptides, nanobodies) and antibodies makes F18 labelling complicated (indirect labelling, modification of the pharmacological properties of the labelled molecule, etc.). The IMoToul project aims to set up innovative radiolabelling techniques adapted to these molecules, based on other radioelements that can be used in PET imaging for cancers and/or neurology, such as Copper Cu64 or Zirconium Zr89. IMoToul will therefore make it possible to develop innovative MRP in neurology and oncology, from radiochemistry to the first human injection, and then to validate them in clinical research and promote them to drug manufacturers. To this end, it is a continuation of the work that led to the structural, functional and scientific developments that today provide ToNIC with the resources and skills in molecular imaging to join forces with Zionexa, a French company dedicated to innovation and industrial development in this field, within the framework of a joint laboratory. This partnership, with strong added value both in terms of scientific (scientific publications, attractiveness) and industrial (patents, licenses, access to market) value, represents a major opportunity for the development of ToNIC's innovation process and a major lever and asset for the development of Zionexa's R&D activities in Toulouse, from radiochemistry to the clinic on a single site.

The general objective of the project is to propose the development of a novel product for the treatment of Crohn’s disease, with the potential to address unmet medical needs. With the present project, we aim at establishing the best pre-clinical conditions, in order to start soon after, Phase-II Clinical studies in Crohn’s disease patients, using oral CVT120165. We will first improve the original formulation of the drug (galenic studies). We will then complement preclinical studies (additional dose-responses) investigating the effects of oral CVT120165 in acute and chronic animal models of Crohn’s disease. We will then test the effects of CVT120165 in organoid cultures from IBD patients, focusing on tissue function recovery. Finally, we will set up the conditions to develop a companion assay, aiming at best identifying patients who would be good responders to CVT120165. PAR-for-Cure (PARCURE) gathers preclinical studies that would set the best conditions for Food & Drug Administration (FDA) presentation of CVT120165 for Crohn’s disease indication.

Irritable bowel syndrome (IBS) is the number one cause of consultation with the gastroenterologist. IBS is characterized by abdominal pain associated with impaired digestive functions. At the present time, there is no diagnostic marker for this pathology which drastically reduces the quality of life of patients, the inclusion of patients in the different subgroups of IBS being made on the basis of clinical questionnaires and by exclusion of other pathologies. This classification is one of the causes of the failure of clinical trials in this very heterogeneous group of patients. The increase in knowledge regarding this pathology and the identification of new therapeutic pathways represents an important challenge to improve the clinical care of these patients. Recent studies have shown that a dysfunction in the communication between the intestinal microbiota and the host could lead to the development of IBS. Thus, a better understanding of host-microbiota relationships could allow us to identify new therapeutic strategies. Numerous reports have established a link between the pathogenicity of IBS and the dysbiosis of the intestinal microbiota, a condition which refers to the decrease / loss of microbial diversity and richness. Nevertheless, there is a difference in the bacterial composition reported by the different studies. Due to the absence of a clear profile of dysbiosis of the intestinal microbiota in IBS and a functional redundancy of bacteria within the microbiota, our main objective is to identify the bacterial compounds implicated in the regulation of pain associated with IBS. Unlike inflammatory bowel disease, no increase in bacterial translocation could be observed in IBS patients indicating that if the bacteria have an impact on visceral pain, this is done through the action of the secreted molecules and / or transformed by bacteria on intestinal homeostasis. As many lipids are able to cross the intestinal barrier, we have attempted to characterize bacterial lipid metabolites. In a previous study we demonstrated that lipopeptides synthesized by bacteria can regulate the activity of sensitive nerves. Recently, we have quantified in the microbiota long chain fatty acids (LCFA) capable of regulating the functions of intestinal epithelial cells. We notably characterized a AGLC hydroxylated on the third carbon, C18-3OH, capable of activating the nuclear receptor PPAR. The objective of our project is therefore to study the role of the AGLC produced by the microbiota in the pathogenicity of IBS and their mechanisms of action on the host. As a first objective, we will establish the link between dysbiosis of the intestinal microbiota and visceral pain by characterizing the implications of the PPAR nuclear receptors in a mouse model of IBS. Then, we will quantify the bacterial AGLC and the abundance of microbiota bacteria during the genesis of IBS in mice. The correlation between these two parameters (bacterial strain and lipid compounds) and the symptoms of mice should allow us to characterize the AGLC and the bacteria involved in the pathogenicity of IBS. In a final part of our project, we will determine the agonist properties of bacterial AGLC on PPAR. Then, in vivo, in mice, we will assess the therapeutic potential of AGLC and of the bacteria involved in their production. This project, based on the complementarity of the different partners, should allow a better characterization of the pathogenicity of IBS. Our consortium offers a unique opportunity to understand the mechanisms of action of these bacterial AGLCs on pain to open new therapeutic perspectives in IBS.

Aging is characterized by a progressive loss of physiological integrity, leading to age associated frailty. The hallmarks of aging include cellular senescence, telomere attrition and metabolic disorders. Remarkably, during aging the liver is one of the first organs displaying these particular traits. In this project, we propose to use complementary expertise and models to explore the interdependence of these different traits of aging. We propose liver senescence as a key hub, and an entry point to a deleterious cascade leading to age related dysfunctions. To this purpose we will test the sufficiency and necessity of telomere attrition and metabolic alterations as potential modulators of senescence in the liver of mouse and zebrafish. The results from our work will help to decipher the chronology of events starting in the liver and leading to the whole-body aging and will help to better design and refine therapeutic strategies.