The objective of the CAPT-ESE project is the development of embedded sensors specific to the equine athlete and his rider, tools to assist training management in the prevention, early diagnosis and treatment of locomotor disorders. Around a consortium bringing together biomechanical researchers, veterinary clinicians and product developers resulting from an industrial partnership structured as an extension of an ANR LabCom, the tools and methods developed will be applied to a dual context of major interest for the equine athlete: 1) work in an aquatic environment for functional rehabilitation 2) management of injuries by adapting sports activity (horse and rider). The project aims at broad research fields on the implementation of expert systems for clinical diagnosis and training monitoring and is part of an E-Health and connected medicine approach applied to the animal. To this end, a complete range of connected objects equipped with biomechanical and physiological sensors (accelerometers, gyroscopes, GPS, skin temperature, heart rate...) will be incorporated into the equipment (saddle, girth, boots) of the horse and also placed on the rider. More specifically, CAPT-ESE aims to test the following 5 hypotheses: - the onboard technologies developed allow precise, repeatable and relevant measurements of locomotor parameters to be obtained in real training conditions and in the aquatic environment; - the measurements obtained with these on-board technologies are, for swimming, correlated with those of an innovative 3D kinematic acquisition system; - the integration of work in the swimming pool allows to improve physical condition by reducing the processes of tendinous and osteo-articular fatigue; - working in an aquatic environment improves the clinical tolerance of spinal injuries; - the position of the rider and the synchronisation of the rider/horse pair modify the biomechanical constraints and the workload. The project revolves around a central work-package in which 20 adult show jumping horses with spinal injuries will be included. The horses will start with 4 weeks of classical mounted work, standardized thanks to the control, by the developed sensors, of the time/velocity/distance/heart rate parameters. The horses will then follow 8 weeks of work in the swimming pool. At the time of inclusion (D0), at the end of the 4 weeks of classic work (S4) and at the end of the 8 weeks with pool work (S12), a complete clinical evaluation of the horses will be carried out (X-ray, ultrasound, MRI, scintigraphy and stress tests). Between these 3 deadlines, the monitoring of locomotion and physiological parameters will be carried out using the sensors developed and integrated into the equipment of the horse and rider. Two other work-packages will be added to the first one using the same horses: - the first aims to test hypotheses relating to the development of kinematic methods in aquatic environments and the analysis of the biomechanics of swimming in horses; - the second one will take advantage of the classical mounted work phases to develop measurement methods to quantify the horse's locomotion and workload and to apply them to the analysis of the interactions of the horse/rider couple. The CAPT-ESE project is a breakthrough in terms of technology (on-board sensors, kinematics in the aquatic environment), methodology (studies combining biomechanical, physiological, clinical and advanced imaging data) and pathophysiology (sports rehabilitation protocols). The whole is converging towards the development of new patentable and marketable products in order to offer expert training monitoring systems.

Endoscopic retrograde cholangiopancreatography (ERCP) is a common therapeutic procedure for the treatment of biliary disorders (stones, cancers). It is a complex interventional endoscopic gesture, performed orally using an endoscope and various passive catheterization instruments. Several operative difficulties significantly impact the ERCP and, in 1 out of 5 cases, access to the biliary tree and progression prove difficult or even impossible. The objective of the MAAGIE project is to develop new tools in order to develop the CPRE gesture towards greater comfort and performance. Other interventional specialties with endoluminal or vascular access such as urology, cardiology, etc. already benefit from means of assistance based on AI, imagery or robotics. On the other hand, because of specific difficulties (poor images quality, complex and variable anatomy, difficult acces) very little research succeded in the field of digestive endoscopy. Our scientific objectives are as follows: 1) Help with planning ERCP thanks to patient-specific 3D digital models, 2) Setting up means for locating instruments by fusion of radio images / digital 3D model, 3) Development and testing of active ancillaries for easier navigation. The introduction of new technologies in CPRE would mark a turning point in this specialty, whose operating methods have remained almost unchanged for 30 years. The MAAGIE project is part of the "Technological transition" theme of this Call for Projects, and meets the specifications of its "Technologies for health" axis. It will be coordinated by ISIR, Sorbonne University. APHP is a partner in the project through two university hospitals (Saint-Antoine, Mondor). The BMBI laboratory of the Compiègne University of Technology and the LIP6 of Sorbonne University complete the consortium.

The temporal coordination by the circadian clock of the rhythms of eating/fasting, activity/rest and wakefulness/sleep with the day/night cycle is an important process in our physiology. Circadian disruption or desynchronization has negative health effects. Skeletal muscle, as a key motor organ, plays a central role in systemic metabolic homeostasis and many aspects of its physiology have circadian rhythms. This link suggests that chrono-modulation could be used to maximize the well-established benefits of exercise on metabolic health. However, the mechanisms linking muscle physiology, circadian time and metabolism remain poorly understood. We have previously identified Krüppel Factor 10 (KLF10) as a circadian transcriptional regulator of hepatic energy metabolism and our preliminary data suggest a similar role in skeletal muscle. The Klf10 gene is strongly induced by high glucose concentrations and acute aerobic exercise in skeletal muscle. Mouse muscles with systemic invalidation of Klf10 show altered fiber ultrastructure, biomechanical behaviour and metabolism. In a recently developed skeletal muscle-specific knockout model (skmKO), we observed altered muscle and fiber biomechanical properties and deregulation of gene expression in myogenesis, mitochondrial metabolism, extracellular matrix and immune response. Our hypothesis is that Klf10 is an important molecular link between energy metabolism, muscle fitness and circadian rhythmicity. We will use the skmKO model with a multidisciplinary approach to (i) define the role of KLF10 in skeletal muscle metabolism, biomechanics and circadian physiology as well as in systemic metabolic homeostasis, (ii) understand how it regulates glucose uptake and signalling, and (iii) analyse its impact on metabolic adaptation to exercise and in the reinforcement of circadian rhythms by daily physical activity. Although the importance of the circadian clock is universally recognized, little or no attention is paid to it, particularly in medical practice. This project will provide valuable information on an emerging family of circadian and metabolic regulators in order to better exploit the link between circadian rhythm and exercise physiology from a preventive and therapeutic perspective.

Many molecules dedicated to therapy are nowadays lately removed from the pipeline of drug discovery, in the clinical phases, because their toxicity or lack of efficacy has not been evidenced in preclinical studies. Researchers and pharmaceutical companies outline the critical need in the development of advanced in vitro trials, looking for human cells based organoids able to improve screening’s efficiency and to reduce the number of animal trials, following the 3R rule. Recent progresses in bioengineering and microtechnology pave the way to “organ-on-chip” devices ensuring 3D cell culture in conditions close to physiology. However, such models are still simplistic and not strongly validated. Based on this analysis, MimLiveronChip proposes a bioinspired approach to mimic the mandatory steps allowing the study of xenobiotic’s toxicity and metabolism in the liver. The original choice is to focus on and to reproduce two key events in series: not only the biotransformation by hepatocytes of substances transported by the blood flow, but also (and upfront), their transfer (hindered or not) across the monolayer of endothelial cells, that are very specific in the liver: they are fenestrated in healthy conditions, and lose these properties in early stages of the pathology (steatosis, fibrosis, …). In this project, we will investigate the relevance of several hypotheses regarding the effect of the mechanical and biochemical micro-environment on this fenestrated status, so as to maintain it or in contrast alter it to mimic pathological cases. Our project also addresses technological issues. As end users, we know that microfluidic devices might appear complex compared to classical 2D culture. Therefore, we propose to develop a fully integrated platform, equipped with flow and pressure controllers, as well as sensors to monitor the cell culture and allow mid throughput assays for drug screening. The newly developed tools will be benchmarked with up-to-date technology employed in CRO or pharma companies. Our goal is to position the organ-on-chip platform in the pipeline of preclinical trials, combining toxicity and metabolism evaluation. This multi-disciplinary project relies on a close collaboration among four teams bringing complementary expertise: hepatic tissue engineering at different scales (UMR UTC-CNRS Biomechanics and Bioengineering); microsystems and biology of endothelial cells (SMMIL-E UMI CNRS), as far as academia is concerned, to which can be added : a SME leader in devices for microfluidic experiments (Fluigent) and a startup dedicated to the development of advanced in vitro trials based on high throughput imaging (HCS Pharma). Preliminary common studies have demonstrated the relevance and the feasibility of the proposed methodology. Regarding socio-economical features, the work performed in our project should allow the reduction of attrition rate for drug candidates in the late clinical stages. This will thus decrease the development costs and duration in the pharmaceutical industry, but also for chemicals, in the framework of REACh regulation, for the assessment of the effect of pesticides, and in agro-industry (nutraceutics). Mid throughput cell culture devices developed in MimLiveronChip can also be used for more fundamental research (system biology, regeneration studies), as they better mimic liver structure and functions. Both companies involved in the project will benefit from direct positive feedback since their portfolio will be enriched with new equipment and screening methods, respectively. Finally, demonstrating the benefit of coupling the endothelial hepatic barrier with the 3D hepatocyte transformation unit will offer many innovative strategy integrating other organs on chip, developed in the academic labs involved in the project.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in western countries. It can be dichotomically divided into steatosis, associated with a benign outcome, and steatohepatitis (NASH), characterized by progression to fibrosis, hepatocellular carcinoma and increased mortality. It is estimated that 24% of European adults develop NAFLD, 10-30% of them will evolve to NASH, among which 10-15% develop fibrosis/cirrhosis. Currently, lifestyle adjustment remains the cornerstone of NAFLD management in the absence of any effective pharmacologic therapy, and the liver transplantation is the only option for NAFLD-related end-stage liver diseases. NAFLD is a complex and dynamic disease whose pathogenesis is poorly deciphered. Understanding of mechanisms involved in NAFLD development and progression is a key step for a better risk stratification. In parallel, pharmaceutical industries face bottleneck to develop new therapies because of the lack of human liver relevant models. Many animal models have been developed to reproduce NAFLD progress but they are not fully relevant due to their specific metabolisms. Simplistic 2D in vitro models are also limited when investigating NAFLD, which involves complex interactions between different cells and cells-extracellular matrix (liver is a complex organ with multicellular organization and most of cells are involved/affected during NAFLD). We hypothesize that the smart design of a complex multicellular NAFLD model will provide an unprecedented tool to investigate this disease. In this project, we plan to address 3 major goals to offer a relevant tool for the follow-up of NAFLD progression and treatment i) development of NAFLD-on-chip model from multicellular liver-on-chip mimicking in vivo liver architecture/physiology using human primary cells ii) identification of mechanisms and biomarkers involved in NAFLD progression and benchmark potential drugs iii) development of an integrated NAFLD mathematical model.