The services in charge of communication and advisor for local scientific culture (SCCS) of the Inserm regional delegations are collectively answering to this ANR call to pool scientific mediation and communication actions of regional and national scope as part of the festival "InScience: cultivate your health with Inserm". This festival is an opportunity to honor the winners JCJC and PRC 2018/19 as well as a way to shed light on a global valorisation of science with many scientific staff from our laboratories and Clinical Investigation Centers. Our main objective is to support throughout three years the scientific staff of this call who will be associated with our local committees. We will rely on their skills, their ideas, their strengths of proposal. These women and men will be warrantors of a clear, popularized and just scientific word. For a better visibility of this festival and of project leaders, we will suggest annually a duo of "researcher/influencer" as godmother/godfather of each edition. This promotion will give us greater visibility on social networks and will allow us to attract other audiences. We have already sought personalities who could take part in these pairs such as Elodie Chabrol, internationally recognized in the field of scientific communication, and Marion Leboyer, psychiatrist and Inserm Grand Prix 2021. It seems important to us to specify that the budget suggested in full cost include the HR costs, which only relate to the valorisation the 18/19 laureates’ work. These human resources cost is just under 0.2 FTEs for an engineer of the selected projects, linked to InScience overall; and relates only to the SCCS that coordinate the project. There is therefore no recruitment to be expected since InScience take place each year with a division of tasks by delegation already established. Locally and by delegation, everything is already thought out and organized in this sense. Lastly, this project is carried by all the regional delegations. Delegations that do not appear in the list of projects are locally associated with universities of partner sites and will submit actions for future editions of InScience in their project.

Neocortical development requires tightly regulated processes, and perturbations lead to malformations (MCDs). Our groups have demonstrated the importance of the cytoskeleton during these key developmental steps. Recently, Cytoplasmic dynein 1, heavy chain 1 (DYNC1H1) mutations were identified in MCDs, as well as in motor neuron degeneration, referred to as « Dyneinopathies ». The wide spectrum of these disorders, together with dynein’s pleiomorphic cellular functions, raise fundamental questions about the effect of mutations on different cellular partners and processes. In this transversal project, we unite molecular and cellular neurobiologists, with clinicians and geneticists. This project will address crucial elements concerning the dyneinopathies, i.e. to find out the various molecular and cellular mechanisms by which disease-related dynein mutations disrupt cellular functions. We will question how distinct mutations perturb dynein’s behavior in patient-derived cells, as well as in mouse progenitors and post-mitotic neurons. Individual genotype-phenotype correlations will advance comprehension of these severe and variable disorders. Our objectives are: · To refine the phenotypic spectrum and natural history of dyneinopathies ranging from fœtus to adulthood, and to understand how DYNC1H1 mutations generate a broad spectrum of phenotypes by correlating phenotype, genotype and protein modelling of mutations, in order to provide clues concerning key and distinct mechanisms perturbed in these disorders. Related to this, we will search for mutations in other genes involved in dynein-dependent pathways. · To assess the biochemical consequences of DYNC1H1 mutations on dynein complexes and to identify their cellular consequences and effects on major dynein-dependent processes in patient-derived fibroblasts, as well as in genome-edited cell lines with different versions of mutant DYNC1H1. · To characterize the effects of selected DYNC1H1 mutations in neuronal progenitors and post-mitotic neurons in the developing mouse cortex. To this end, we will begin by studying a new Dync1h1 knock-in mouse mutant carrying the p.Lys3334Asn mutation responsible for human MCD, identifying perturbed cellular mechanisms during cortical development. These data will be compared with an existing mouse mutant model (Legs at odd angles (Dync1h1 +/Loa) that shows subtle cortical defects and a slow motor neuron loss similar to « peripheral dyneinopathies ». We will thus shed light on perturbed mechanisms specifically affecting cortical development and leading to MCDs, versus other mutations affecting motoneuron survival and potentially disturbing different dynein functions. Importantly, we will determine whether individual mutations may lead to loss of function effects while others may lead to gain of function or dominant negative effects. These experiments will provide major information on the molecular mechanisms leading to the different pathologies as well as strongly increase our knowledge on the in vivo regulation of the dynein motor. We will characterize the critical roles of mutated DYNC1H1 during proliferation, migration and differentiation of neurons in the cortex. Such studies may distinguish MCD from peripheral (SMA-LED) phenotypes and help determine pharmacological interventions, necessary in each case. In addition to exploration of the proposed pathophysiological mechanisms, these studies could have diagnostic implications, especially to assess the pathogenic effect of some rare variants for which conclusions are difficult to draw. This information will be important to better classify patients and identify those requiring early specialized care. In addition, this work will pinpoint different facets of dynein function, involving its numerous partners and the microtubule cytoskeleton, in cortical development.

Acute kidney injury (AKI) is a life-threatening disease with high mortality characterized by an abrupt decrease of the kidney glomerular filtration rate, extra-kidney consequences (cardiovascular diseases, lung injury, neurological impairment) and high risk of secondary chronic kidney disease. The cost of AKI is very high and substantial cost savings may be yielded by the development of new preventive and management strategies. SpareKid aims to predict the development of AKI to allow dedicated primary prevention. AKI is an extremely complex disease perfectly exemplified by the current inability to successfully predict the development of AKI before the attack, even in a well-controlled clinical setting such as cardiac surgery or chemotherapy. The complexity of AKI leads to a huge heterogeneity of the kidney response even after an insult of similar intensity, which strongly impedes the personalized management of individuals in AKI at-risk situations. These data also suggest that AKI should be better described as a maladaptive kidney response to the insult. Therefore, the first innovative concept of SpareKid is to define a so-called non-invasive Kidney Resilience Index (KRI). The second innovative concept of SpareKid is to define the KRI based on in-depth and multiscale molecular and clinical data using a holistic big data-based strategy to integrate high throughput urinary and plasma proteomic, immunologic signatures (bulk-RNA sequencing and characterization of immune cell populations), and genetic signatures (whole-genome sequencing) and detailed clinical parameters. Last, using data from the National Systems of Health to model the potential cost-effectiveness of new predictive algorithms developed, we will assess the cost of each clinical trajectory according to the outcomes (AKI, CKD, death) of patients, the cost sparing of a preventive strategy and ultimately proposed a new methodology for randomized clinical trials in AKI to improve their cost-effectiveness.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae that principally infects macrophages and Schwann cells. Leprosy remains a major public health problem with more than 200,000 new cases reported in 2014. Leprosy reversal reactions (RR) correspond to acute episodes of cellular immunity in skin and/or nerves classically observed soon after the treatment was initiated and are the leading cause of permanent neurological damage. Thus, the early identification of patients at risk of RR is one of the most decisive challenges in modern leprosy care. Why only a proportion of leprosy patients undergo RR is not known. Recently, we have conducted a transcriptomic study demonstrating that RR patients have a genetically controlled disregulation of the inflammatory response against M. leprae. We hypothesized that, as observed in numerous infectious diseases, the most extreme forms of RR could result from a collection of genetically diverse single-gene inborn lesions. Our first objective is to test this hypothesis and identify the genetic variants that have a very strong effect in the development of the most severe RR by a cutting-edge strategy combining phenotypic screening for extreme forms of RR in a large sample of leprosy patients enrolled over the last 15 years and whole genome sequencing of these severe RR forms followed by ad hoc functional studies. Buruli ulcer (BU) is another chronic mycobacterial infectious disease caused by M. ulcerans and clinically characterized by extensive destruction of the skin and soft tissues as well as bone lesions. BU incidence is increasing and is now the third most common mycobacterial disease worldwide. It is estimated that about 25% of BU patients — particularly children under the age of 15— become permanently disabled. A remarkable observation is that in ~20% of the patients who received antibiotics, antimicrobial killing is accompanied by clinical deterioration, known as paradoxical reaction (PR). Although little is known on the biological mechanisms governing this event, it is considered as an immune reconstitution inflammatory syndrome (IRIS). Our recent report of the first Mendelian cases of BU in a consanguineous Beninese family, our preliminary results of the first GWAS on BU and the observation that FVB/N mice spontaneously heal while other strains could not control the disease support the view that the considerable variability in the clinical presentation of BU – in particular the onset of PR– can be accounted for by host genetic factors. IRIS have been observed in a number of immunosuppressive conditions, however, the similarity of PR with RR is puzzling as they are both pro-inflammatory reactions following the start of antimicrobial treatment occurring in patients not known to be immuno-deficient. We hypothesize that PR observed in BU share, at least to some extent, common mechanisms with RR observed in leprosy. Our second objective is to test this hypothesis by comparing the RNAseq transcriptomic profiles observed in PR to the ones observed in RR and by assessing through association study of the largest sample of PR worldwide the role of the genes that will be identified as relevant in severe and common RR. Our project is groundbreaking, as RR and PR are not generally thought to be genetic disorders. However, it is achievable, as it builds on strong phenotypic data, already available biological samples, powerful NGS technology, long-lasting collaboration and expertise of the two participating laboratories. This work has both immunological and clinical implications. The discovery of molecules and pathways involved in RR and PR will help us to understand the relationships between the host, antibiotics-based treatment and mycobacteria in natura. The genetic dissection of RR and PR will facilitate novel preventive and therapeutic approaches based on an understanding of the pathogenesis of these two major causes of permanent sequelae in the poorest countries of the world