The mature nervous system is an intricate network in which neurons are connected to specific partners. The choice of these partners is crucial for the correct behavior of the network and is determined at very early stages of development. In the visual system, retinal axons have two levels of organization in their main primary targets, the dorso lateral geniculate nucleus (dLGN) and the superior colliculus (SC). In the dLGN the retinal axons coming from both eyes segregate in two non-overlapping territories. In the dLGN and in the SC, retinal axons are topographically organized in their targets: the temporo-nasal axis of the retina projects on the rostro-caudal axis of the SC, in an ephrin-A-dependent manner. Both level of organization are dependent on cAMP signaling. Among the nine transmembrane adenylyl cyclases – the cAMP synthesizing enzymes – only adenylyl cyclase 1 (AC1) is crucial for the appropriate development of retinal maps, although other ACs are expressed in the retinal ganglion cells (RGCs) and their targets. cAMP regulates a large range of cellular processes and axonal growth cone behaviors, from emergence, outgrowth, and stabilization or elimination of individual filopodia, to turning and retraction. However the mechanisms by which this ubiquitous messenger regulates specifically such spatially and temporally restricted behaviors are still poorly understood. Compartmentalization of cAMP is thought to explain the activation of distinct cAMP-dependant signaling pathways. Microdomains of cAMP have been imaged in cardiac myocytes. In neurons, indirect evidence suggests their presence, but the components of these microdomains are unknown. Our project aims to determine the composition of microdomains structuring cAMP signaling and to find out if they are critical for the formation of appropriate neuronal networks. Additionally, we will investigate the potential interactions between these microdomains. We identified three candidates with characteristics that make them potential structural organizers of cAMP signals: lipid rafts, focal adhesions, and the anchoring proteins AKAPs (A kinase anchoring proteins). The project will follow the subsequent plan: 1. Identification of cAMP microdomains required for the development of the visual system (test of the 3 candidates: lipid rafts, focal adhesions, and AKAPs) 2. Importance of adenylyl cyclase 1 targeting to microdomains 3. Interactions between the identified microdomains The expected results will increase our knowledge of the mechanisms required for the development of neuronal networks, and together with other studies will in time participate to a better understanding of developmental disorders of neuronal networks, and of the absence of axonal regeneration after lesion in the central nervous system. Many aspects of our study involve molecules affecting axonal regeneration. cAMP is an enhancer of axonal regeneration in the optic nerve and the spinal cord. A subset of axon guidance cues including ephrins are potent inhibitors of axonal regeneration after lesion. The lipid rafts structuring proteins flotillins are overexpressed after lesion of the optic nerve in goldfish, an organism in which axons of the central nervous system regenerate. Our project will provide important insights into the contribution of each of these molecules to axonal regeneration (or lack of axonal regeneration).

Dark matter is paramount for understanding our universe. It is five times more abundant than ordinary matter, and it is responsible for creating the potential wells in which ordinary matter fell to form galaxies and stars. However, the fundamental nature of dark matter remains unknown. Discovering the particles it consists of and understanding their interactions would therefore also mean unravelling new fundamental laws of nature. The importance of dark matter for particle physics, cosmology and astrophysics has placed it in the forefront of the experimental and theoretical research in these fields. Current observations suggest that the particle-physics dynamics of dark matter may be quite rich, and rather different from long-held expectations: The comparable amounts of dark and ordinary matter indicate that the dark matter density may be due to an excess of dark particles over dark antiparticles, an asymmetry, dynamically related to the ordinary matter-antimatter asymmetry. Moreover, the observed galactic structure can be explained better if dark matter possesses sizeable self-interactions rather than being collisionless. In recent work, I explored the high-energy physics that could relate the dark and ordinary matter abundances, within the asymmetric dark matter scenario. I constructed detailed particle-physics models, and demonstrated that they provide a very suitable host for self-interacting dark matter. Furthermore, I showcased that the complicated cosmology which self-interacting dark matter typically implies, has important consequences for its phenomenology today. The proposed project aims to fully develop this new paradigm of self-interacting asymmetric dark matter along two paths. First, I plan to compute in a comprehensive way the cosmologies of models of dark matter with long-range self-interactions. Second, using this as input, I aim to work out consistently the direct and indirect detection signatures of these theories. I expect the results to inform and guide experimental searches and numerical studies of dark matter.

RESUME PROJET – Contexte scientifique et objectifs: La découverte d'un traitement efficace de l'arthrose représente un enjeu majeur pour la prochaine décennie. L'arthrose se caractérise par la perte progressive du cartilage articulaire et un épaississement de l'os sous-chondral. Les cytokines proinflammatoires, en particulier l'IL-1 jouent un rôle essentiel dans l'arthrose. Récemment, la découverte de l' inflammasome pourrait expliquer la sécrétion intensive d'IL-1 observée durant la dégradation cartilagineuse. L'inflammasome est un complexe multiproteique, responsable de l'activation des caspases et conduisant à la sécrétion d' IL-1. Les NALPs sont les protéines centrales du complexe. L'ASC, autre composant essentiel, relie les NALPs à la caspase 1. Des mutations dans le gène NALP3 sont responsables de maladies inflammatoires._x000D_ Objectifs: étudier l'expression des différents composants de l'inflammasome (dans os, cartilage), décrypter la régulation du gène NALP3, comprendre le rôle de l'inflammasome dans la destructruction articulaireRESUME PROJET – Description: A partir de différents modèles de culture, culture primaire de chondrocytes et ostéoblastes humains normaux et arthrosiques, explants de cartilage costaux de souris et chondrocyte articulaire de souris (de souris sauvage ou de souris génétiquement modifiée (souris KO invalidées pour NALP-3, ASC ou caspase-1), nous étudierons l'expression des différents composants de l'inflammasome à la fois dans le cartilage et l'os. Nous appliquerons deux types différents de stimuli (stimulation par l'IL-1 et compression) et analyserons par RT-PCR quantitative, western-blot et immunohistologie l'expression en ARNm et en protéine des NALPs, d'ASC et de la caspase-1. Nous décrypterons ensuite la régulation du gène NALP-3, en clonant le promoteur humain NALP-3 et analyserons la fonction de ce promoteur par analyse de CAT, bandshift et expériences de ChIP. Enfin, nous évaluerons le rôle de l'inflammasome dans la destruction articulaire en utilisant différentes stratégies pour inhiber l'inflammasome (le siRNA, les souris KO et un modèle in vivo de souris arthrosique, modèle utilisant la section de ligament et la meniscectomie du genou). Puis, nous mesurerons la production de PGE2, les expressions de cyclooxygenases et de prostaglandine E synthases ainsi que les expressions de MMP-1, -3 -13.RESUME PROJET – Resultats attendus: Bien qu' IL-1 soit la cytokine la plus connue et la plus puissante impliquée dans la dégradation articulaire durant l'arthrose, les premières tentatives afin de contrecarrer son effet (utilisation d'IL-1RA) n'ont pas été très concluantes. Une meilleure compréhension de la relation entre le processus de sécrétion d'IL-1 et l'arthrose en physiopathologie devrait être utile pour définir de meilleures cibles thérapeutiques.

Surgery is a lifelong learning endeavour, much of which happens through mentoring: when a mentee surgeon operates side-by-side with an expert mentor. However, mentees cannot always access experts for training. While remote collaboration systems aim at breaching this gap by making expert surgeons available remotely, they do not fully support surgical work as they focus on supporting the transmission of instruction, rather than the transmission of knowledge. TELEMENTOR is a human–centred project drawing from Human–Computer Interaction (HCI) methods, with an original approach to supporting mentoring remotely by drawing from social and learning science theories, to design, build, and evaluate tools that support remote training during physical tasks. The outcome will be tools through which experts not only can provide distant instructions, but also novices can effectively acquire new knowledge from experts. To achieve this, we will first (WP1) expand the knowledge of surgical mentoring, understanding the learning needs that inform a mentor in making decisions on their apprenticeship method. Then, using this understanding, we will (WP2) create tools where remote experts become active participants in the creation of mobile views, so they can gather information necessary for effectively transmitting knowledge. Following, we will create dual-user gesturing tools where mentees can interact with digital information while performing physical tasks, enabling them to express information to the remote expert that can inform the latter in adapting their mentoring strategies. Finally we will (WP4) integrate the two techniques and institutionalize them by deploying the final result at a teaching hospital, to study their situated use. TELEMENTOR will create tools that increasing the mass of surgical talent, contributing towards the democratisation of healthcare and to decreasing its costs.