Malaria remains a major cause of death and morbidity worldwide affecting 200 million people annually. Plasmodium falciparum (P. falciparum) is responsible for the majority of the 500,000 deaths attributed each year to malaria, but P. vivax, although less virulent, contributes significantly to malaria morbidity. The infection in humans is initiated by the bite of an infected mosquito which inoculates the parasite into the skin. The parasite then migrates to the liver where it interacts with non parenchymal cells (NPC) before invading the hepatocytes within which it replicates. Once mature, the parasite passes into the blood initiating the erythrocytic stage of its development which is associated with the disease symptoms and transmission. Targeting the parasite before of during its development within the liver is thus an ideal target for prophylactic approaches. But the search for novel or improved means to eliminate malaria necessitates appropriate experimental models. So far, most if not all of our basic knowledge on the parasite-host interactions during the liver stage comes from murine models of experimental malaria. Although these models have non questionable advantages, they do not recapitulate the biology of the human host cells and of the human malaria parasites. There is thus a critical need for developing novel and innovative tools, biologically more relevant to humans for the identification of novel therapeutic targets. Additionally, in vitro studies on P. falciparum or P. vivax liver stages, including screening for new antimalarial compounds, are so far routinely performed using 2D cultures of human hepatocytes within which the parasite development is not efficient and is incomplete. Moreover, these 2D systems recapitulates only partially the physiology of the host cell and do not reproduce the complex 3D architecture of the liver. Yet, it is clearly established that heterotypic cell interactions and 3D systems improve human hepatocyte functions and the predictivity of drug metabolism and toxicity assays. Finally, these 2D monocellular systems preclude any study of the interactions between the parasite and liver NPC which are, so far, largely unknown for human malaria parasites. In this context, and based on the partners extensive knowledge of human Plasmodium liver stage and human hepatic cells isolation and culture, we propose to develop new 3D organoid culture systems, including multicellular systems composed of human hepatocytes and NPC, in order to improve in vitro liver stage development, to assess the cross-talk between the parasite and the NPC and evaluate efficacy of chemotherapeutic and immunoprophylatic interventions targeting Plasmodium liver stages. Finally, implementation of this project will provide marketable systems for applied research in malaria but also in other hepatotropic pathogens.

Evolution has provided effective ways of protecting man from external dangers while prospering from opportunities. The gut microbiota is a complex mixture of microbes that are continuously challenging the integrity of the intestinal barrier while at the same time providing numerous metabolic advantages. The intestinal barrier integrity is ensured by various mechanisms including host antibodies in the form of secretory IgA (sIgA). sIgA binds microbes and regulate microbiota ecology. Patients suffering from IgA deficiency display altered microbiota ecology and increased risk of infection. Our project will provide preclinical evaluation of a therapeutic approach aiming to reconstitute IgA in immune deficient individuals. This will provide a better insight into the role of IgA in regulating host - gut microbiota interactions and potentially provide evidence for a protective therapy in immunodeficient pathologies, such as primary as well as corticosteroid induced immunodeficiencies.

Observing a decline of interest in academic careers in medicine, both in France and internationally, this research focuses on the factors underlying career choices made by young physicians. We suspect that the decline in medical academia may be in part due to an insufficient recruitment of women that starts at the beginning of the training curriculum, and we hypothesize that the ideal mentoring/guidance/selection process of young female physicians may not be identical to the one ideal for young male physicians and that it is part of a complex and multifactorial set of individual and organizational factors. The aims of this project are to assess, with a mixed methodology (quantitative survey, interviews, archival analysis and observation), the respective contribution of different factors involved in career choices. Among these variables, some of which are already identified in the literature as predictive (mentoring and role models, perceived discrimination), others are identified but controversial (attitude toward research, work-life balance), and others are present in the area of counselling psychology, but have not yet been invoked to report on choosing a career in academic medicine (congruence of values between an organization-the academic community- and the individual, learning experiences, and several variables of personality: anxiety, stress, intrapreunarial self-capital). To provide a better understanding of the levers and barriers to engagement in academic careers in medicine, a first quantitative study is planned. This survey will be administered to the population of interns and fellows in France (N= 44,000) and will measure the variables invoked in the decision of a career choice in academic medicine and to articulate these variables within a global integrative model accounting for gender specific effect based on knowledge on the field of guidance psychology and educational sociology and inspired by Lent's theory. These quantitative analyses will be followed by a qualitative study from a retrospective point of view. Forty in-depth semi-structured interviews will be conducted with several women and men who have successfully completed an academic career in the field of medicine. These interviews will attempt to retrace their perceived career (trajectories) to identify critical periods during which they encounter difficulties or supports. Analysing the development of professional identity in regard with positive and negative experiences during the training course and after can provide a better understanding of individual dynamic over time and confirm our conclusions from study 1. The first two studies will provide elements on the influence of the proximal environment in individual decisions. However, beyond individual choices, we can also consider that the institution plays an active role in "designating" potential candidates for an academic career. The objective of the third study will be to analyse in a more specific way and by a mixed methodology (observation, archival analysis, interviews) the role of the institution in periods which could prove to be decisive during the curriculum: the choice to do or not a Master's degree and the process of becoming a fellow. Given serious consideration to the suggestion that individuals choose what they are chosen by, the aim is to highlight the institution’s role in framing personal and professional aspirations and producing a the range of possibilities. Beyond the contribution of new scientific knowledge on this issue, our consortium makes changing this situation, so that women have easier access to academic positions, central to its work. This is facilitated by the structure of our consortium, which brings together experts in the humanities and social sciences (psychology and sociology) and physicians who will be able to play the role of brokers of this knowledge to institutions (medical schools and national organizations) and residents in medicine.

Malaria is still a major public health problem in 2018, since this infection due to the Plasmodium parasite, present in 91 countries, kills more than 440,000 people every year, with a majority of African children. As observed in most of infectious diseases, the emergence of resistant strains of P. falciparum toward antimalarials is nowadays responsible for a major concern, especially regarding the increasing resistant rate observed toward artemisinin derivatives (ref. treatments for P. falciparum malaria) in Asia, and the subsequent development of multi-resistant strains that could spread worldwide without any therapeutic option. Then, to bypass parasitic resistance, new antimalarials are expected to be active on artemisinin-resistant strains and to possess a novel mechanism of action. It is also crucial to develop new molecules targeting both the asexual (hepatic and erythrocytic) and sexual (gametocytes) stages of the parasite, in a view to block malaria transmission. We previously identified a multi-stage acting lead compound in the thienopyrimidinone series, called Gamhepathiopine (or M1), which fulfills these criteria by acting on erythrocytic, hepatic and sexual stages of P. falciparum. This original molecule displays excellent in vitro activities even on the artemisinin-resistant parasites. In addition, our lead molecule does not exert its antiplasmodial activity by a mechanism of action already described for marketed antimalarials. Such promising results are however tempered by a rapid hepatic metabolization and a poor aqueous solubility, which limit gamhepathiopine activity in vivo. In this context, we thus propose to pharmacomodulate gamhepathiopine to optimize its physico-chemical and pharmacokinetic properties and to potentiate its in vivo activity. To this aim, the metabolic stability issue will be addressed by modifying the two identified sites of metabolization of gamhepathiopine. In addition, the aqueous solubility will be improved by introduction of polar groups and/or synthesis of hydrophilic prodrugs. Additional pharmacomodulation work is also proposed in order to identify new antiplasmodial leads and to modulate the purine-analog character of the scaffold, in the hypothesis of a mode of action related to plasmodial kinase inhibition. The new molecules will be evaluated in vitro on the erythrocytic stages (sensible and resistant strains) and for their cytotoxicity. The most active compounds will be studied 1) for their mutagenicity 2) in vitro against hepatic stages ( (P. yoelii, P. falciparum and P. vivax and for their action on gametocytes and their capacity to block parasite transmission to Anopheles (vector of malaria)) then 3) in vivo, after potential preparation of lipidic nanoemulsions, on a murine model either infected by P. yoelii or humanized and infected by P. falciparum or P. vivax to validate the benefit of the chemical modifications toward PK properties and guarantee the preservation of the multi-stage acting properties. The last part of the project concerns the identification of the gamhepathiopine plasmodial target, in a view to elucidate its novel mechanism of action. A first hypothesis based on M1 chemical structure (purine analogue) and on recent literature data consists in postulating the possible involvement of a plasmodial kinase to explain its antiplasmodial activity. A phospho-proteomic study will thus be conducted to answer this question. In parallel and to extent the study of the mechanism of action of the lead molecule to potential non-kinase targets, an affinity chromatography procedure will be applied to Gamhepathiopine (immobilized on a solid support via a spacer) to try to isolate its target from a plasmodial lysate and to proceed to its identification by MALDI-TOF.

The aim of this project is to fabricate and evaluate an in vitro 3D model representative of the processes of osseointegration and soft tissue integration of dental implants, using Bioprinting techniques, in order to serve as a reliable and reproducible platform for research in implant dentistry. In the same model, an alveolar bone model, a gingival tissue model and a dental implant will be combined: this combination represents the main originality of the model. The development of this model will offer a new tool for basic and clinical researchers, to better understand dental implants integration physiology and peri-implantis development, and to evaluate new biomaterials and drugs. This model will enhance the relevance of in vitro studies, and reduce the use of animal experiments. The research consortium comprises 4 research groups specialized in Tissue engineering, implant dentistry, immunology and bioprinting, as well as a French company in implant dentistry