ERC FUNDED PROJECTS

"Translational research aims at applying mechanistic understanding in the development of "precision medicine", which depends on precise diagnostic tools and therapeutic approaches. Cancer therapy is experiencing a switch from non-specific, cytotoxic agents towards molecularly targeted and rationally designed compounds with the promise of greater efficacy and fewer side effects. The two cell-cycle kinases CDK4 and CDK6 normally facilitate cell-cycle progression but are abnormally activated in certain cancers. CDK6 is up-regulated in hematopoietic malignancies, where it is the predominant cell-cycle kinase. The importance of CDK4/6 for tumor development is underscored by the fact that the US FDA selected inhibitors of the kinase activity of CDK4/6 as "breakthrough of the year 2013". Our recent findings suggest that the effects of the inhibitors may be limited as CDK6 is not only involved in cell-cycle progression: ground-breaking research in my group and others has shown that CDK6 is involved in regulation of transcription in a kinase-independent manner thereby driving the proliferation of leukemic stem cells and tumor formation. We have now identified mutations in CDK6 that convert it from a tumor promoter into a tumor suppressor. This unexpected outcome is accompanied by a distinct transcriptional profile. Separating the tumor-promoting from the tumor suppressive functions may open a novel therapeutic avenue for drug development. We aim at understanding which domains and residues of CDK6 are involved in rewiring the transcriptional landscape to pave the way for sophisticated inhibitors. The idea of turning a cancer cell's own most potent weapon against itself is novel and would represent a new paradigm for drug design. Finally, the understanding of CDK6 functions in tumor promotion and maintenance will also result in better patient stratification and improved treatment decisions for a broad spectrum of cancer types."

2 497 520 €

Start date: 2016-09-01, End date: 2021-08-31

Understanding the links between neuronal plasticity which underlies memory and energy metabolism is a major goal of brain studies. The brain is a main energy consumer and the central regulator of energy homeostasis, and it prioritizes its own supply over peripheral organs. Interestingly, our work demonstrates that the brain is also able to regulate its own activity under energy shortage to favor survival. The EnergyMemo project proposes to perform in drosophila an original integrated study of the interplay between energy metabolism and olfactory memory at the molecular, cellular and circuit levels. On the ground of important preliminary results, we will investigate in vivo how and why the energy flux increases during long-term memory encoding, and how brain plasticity is regulated by the energy supply. We will focus on three major challenges: * Objective 1: to improve our understanding of brain physiology, we will characterize in drosophila neuronal circuits that integrate information about the brain energy status. * Objective 2: to understand how abnormal levels of energy can affect the brain, we will analyze how the energy level shapes the functioning of the olfactory memory center. * Objective 3: to characterize how energy stores are mobilized during memory formation, we will investigate how the neuronal and glial networks interact to manage the energy fluxes. This multidisciplinary project will benefit from our team's longstanding experience in behavioral studies and leadership in live brain imaging, in addition to the unmatched descriptive power of drosophila neuronal circuits at the single-neuron resolution. Successful completion of this program will surely uncover mechanisms of brain function conserved across species, and should bring-up new ideas about how deregulation of energy metabolism can affect cognitive functions in human. Thus the EnergyMemo project could have a major impact in neuroscience from fundamental research to human applications.

2 499 500 €

Start date: 2017-10-01, End date: 2022-09-30

The prefrontal cortex (PFC) subserves decision-making and executive control, i.e. the ability to make decisions and to regulate behavior according to external events, mental models of situations, internal drives and subjective preferences. Our overall aim is to understand the functional architecture of the human PFC and computational mechanisms of PFC function. The PFC function is known to operate along three major dimensions, namely the affective, motivational and cognitive control of action subserved by the orbital, medial and lateral sectors of the PFC, respectively. In this project, our specific objectives are to solve the following three open issues of critical theoretical significance: (1) the functional organization of motivational control in the medial prefrontal cortex; (2) the mechanisms that enables the PFC to control the learning of representational sets required for cognitive control; (3) the functional interactions between the medial and lateral prefrontal cortex, i.e. the integration of motivational and cognitive control into a unitary decision-making and control system. We will address these theoretically and methodologically challenging issues by elaborating computational models that integrate learning and control mechanisms, and in relation to these models, by conducting functional magnetic resonance imaging experiments in healthy humans. The project is expected to significantly improve our knowledge of the human PFC function. This basic project has potential major implications especially in medicine, because alterations of the prefrontal function is observed in aging and most neuropsychiatric diseases, as well as in technology for developing artificial and robotics intelligence with human-like adaptive reasoning and decision-making abilities.

2 500 000 €

Start date: 2010-05-01, End date: 2016-04-30

"NeuroImaging systems are invaluable tools in the understanding of the brain both for fundamental research and clinical diagnosis. However, recent improvements in deep brain imaging technology have been somewhat limited because most of them are based on incremental innovation of mature techniques (EEG, PET and fMRI) instead of breakthrough. In FUSIMAGINE, a genuinely new functional brain imaging modality will be developed and validated whose performances could have a major impact in neuroscience from fundamental research to clinical applications. This new modality is based on the use of ultrafast ultrasound scanners able to reach more than 10 000 frames per second (fps) compared to the usual 50 fps in conventional ultrasound scanners. This concept relies on compounded plane wave transmissions introduced by my team and demonstrates up to 100-fold increase in the sensitivity of blood flow measurements. It enables to image the subtle hemodynamic changes in small brain vessels and thus brain activity thanks to neurovascular coupling. Functional Ultrasound (fUS by analogy to fMRI) is a real breakthrough in brain imaging as our project will demonstrate that: in neuroscience, fUS provides a unique real time, portable and deep brain functional imaging technique for awake and even freely moving small animal imaging, moreover with unprecedented spatiotemporal resolution (~100µm, 50ms). in clinical diagnosis, fUS provides a unique bedside neuro-imaging system of newborns brain activity through the fontanel window. Such real time system will permit to monitor and better understand neonatal seizures and hemorrhages. On adults, fUS provides a unique functional imaging modality during neurosurgery to predict the cortical mapping remodeling resulting of tumor development (such as low-grade gliomas). Finally, new adaptive skull bone correction techniques implemented on the system will enable us to perform non invasive transcranial fUS imaging on human adults through the temple bone."

2 497 603 €

Start date: 2014-05-01, End date: 2019-04-30

A fundamental question in neuroscience is how the biophysical properties of synapses shape higher network computations. The hippocampal mossy fiber synapse, formed between axons of dentate gyrus granule cells and dendrites of CA3 pyramidal neurons, is the ideal synapse to address this question. This synapse is accessible to presynaptic recording, due to its large size, allowing a rigorous investigation of the biophysical mechanisms of transmission and plasticity. Furthermore, this synapse is placed in the center of a memory circuit, and several hypotheses about its network function have been generated. However, even basic properties of this key communication element remain enigmatic. The ambitious goal of the current proposal, GIANTSYN, is to understand the hippocampal mossy fiber synapse at all levels of complexity. At the subcellular level, we want to elucidate the biophysical mechanisms of transmission and synaptic plasticity in the same depth as previously achieved at peripheral and brainstem synapses, classical synaptic models. At the network level, we want to unravel the connectivity rules and the in vivo network function of this synapse, particularly its role in learning and memory. To reach these objectives, we will combine functional and structural approaches. For the analysis of synaptic transmission and plasticity, we will combine direct preand postsynaptic patch-clamp recording and high-pressure freezing electron microscopy. For the analysis of connectivity and network function, we will use transsynaptic labeling and in vivo electrophysiology. Based on the proposed interdisciplinary research, the hippocampal mossy fiber synapse could become the first synapse in the history of neuroscience in which we reach complete insight into both synaptic biophysics and network function. In the long run, the results may open new perspectives for the diagnosis and treatment of brain diseases in which mossy fiber transmission, plasticity, or connectivity are impaired.

2 677 500 €

Start date: 2017-03-01, End date: 2022-02-28

The hair bundles of the sensory cells play a central role in the processing of sounds by the cochlea. Various performances of auditory perception depend upon what biophysical and physiological environment the operating hair bundle can provide to its mechanoelectrical transduction (MET) channels. The project aims at building a more integrated view of the way the hair bundle works. Reaching this goal, requires to understand the interdependence of its functional building blocks and their dynamic interplay. To this purpose, the objectives of the work are : 1. To assemble components of the basal MET machinery The work aims at a) identifying the molecular players of the basal MET machinery, most of which are still unknown b) deciphering their functional interactions, c) developing a simple and efficient tool to validate candidate components of the MET machinery. 2. To elucidate the coupling between MET and stereocilia F-actin polymerisation The work aims at a) characterising this coupling, both in development and in steady-state condition, b) deciphering the role of tip-link tension and Ca+2 influx through the MET channel, c) developing a coarse-grained mathematical model of this coupling, experimentally testable. 3. To understand the interplay between MET, waveform distortions, and masking The work aims at a) deciphering biochemical characteristics of the top connectors, b) explaining why large waveform distortions vanish in the absence of top connectors, c) determining how the operating outer hair cell (OHC) hair bundle contributes to the masking effect in auditory perception. The hair bundle is a highly vulnerable structure, actually the main target structure of noise-induced hearing loss and hereditary deafness forms. As such, advances in the understanding of the mechanisms underlying its functioning will pave the way for the development of therapeutic approaches.

2 495 000 €

Start date: 2012-12-01, End date: 2018-08-31

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease world-wide. HCV-induced end-stage liver disease such as liver cirrhosis and hepatocellular carcinoma represent a major concern in global health. Treatment options for chronic hepatitis C are limited and no vaccine against HCV infection is available. Vaccine development is hampered by several obstacles. High viral variability and escape from host immune responses render antigen selection a major challenge. Antigen selection requires thorough studies to identify conserved T cell and neutralization epitopes and to decipher neutralization mechanisms, aiming to discover the optimal viral target for immune responses counteracting HCV escape strategies. At the same time it is important to develop antigen presentation systems that are efficient in patients with impaired antiviral immune responses, as often observed during chronic hepatitis C. While most vaccine development programs are based on improving HCV cellular immunity, it is essential to associate, in a same vaccine formulation, immunogens able to induce broad spectrums neutralizing and cellular responses. Owing to recent progresses in the field, here we propose a project aiming to overcome the current limitations in vaccine development by addressing the improvement of B cell responses targeting HCV infection. This will be achieved by a detailed investigation of: 1) mechanisms of antibody-mediated neutralization and escape, 2) impact of lipoproteins associating with the viral particle during assembly/release and counteracting neutralization and 3) cell entry steps that can potentially be targeted by antibodies, including those that are not induced naturally. Thus, through the combined expertise of the team in molecular virology, immunology, clinical hepatology and vectorology, we aim to rationalize the development of B cell immunogens and neutralizing antibodies for novel antiviral immunopreventive strategies targeting HCV infection.

2 447 357 €

Start date: 2009-04-01, End date: 2014-12-31

"Homeoprotein (HP) signaling designates the ability of HP transcription factors to transfer between cells, thus acting as signaling molecules. We will investigate several properties of this novel signaling pathway in the CNS and how it can shed light on brain development and physiology, also neurological and psychiatric pathologies. The studies will concentrate on 4 HPs (Engrailed1/2, Otx2 and Pax6) illustrative of the HP family and of high physiological interest. Mouse lines will be developed in which the extracellular expression of single chain antibodies against these HPs can be induced at specific places and times, allowing us to follow the consequences of neutralizing extracellular HPs while preserving their cell autonomous functions. With this tool (and others) we shall study if (and how) HP transfer regulates boundary position in the neuroepithelium and direct cell/axon migration and guidance. In postnatal development, we will dissect how Otx2 regulates the opening, closure and reopening of critical periods in the cortex and controls the behavior of neuronal networks throughout life. Also in the adult we will follow how HPs regulate the physiology and survival of distinct neuronal groups, including midbrain dopaminergic neurons. We shall analyze the physiological interactions between HPs and classical signaling molecules and identify HP targets, in particular those regulating the cell energy metabolism, and explore their ability to modulate the epigenetic state of the chromatin. Using Otx2 and Engrailed as baits, we shall identify the complex sugars with which they interact at the cell surface to get an entry into the ""sugar code"" that confers specificity to HP capture by distinct cell populations. This project should identify new HP functions and highlight them as part of a major mode of signal transduction in the developing and mature CNS. It is expected that this will modify the way we look at many developmental, evolutionary and physiological mechanisms."

2 499 995 €

Start date: 2014-03-01, End date: 2019-02-28

"Because of its biological complexity, cancer is still poorly understood. Chronic inflammation has been shown, both experimentally and epidemiologically, to be a predisposition to, and also an inseparable aspect of clinically prevalent cancer entities. Therefore, a detailed understanding of both tumour and immune cell functions in cancer progression is a prerequisite for more successful therapeutic startegies. My team was the first to reveal the lymphocyte-intrinsic PKC/NR2F6 axis as an essential signalling node at the crossroads between inflammation and cancer. It is the mission of this project to identify molecular signatures that influence the risk of developing tumours employing established research tools and state-of-the-art genetic, biochemical, proteomic and transcriptomic as well as large scale CRISPR/Cas9 perturbation screening-based functional genomic technologies. Defining this as yet poorly elucidated effector pathway with its profoundly relevant role would enable development of preventive and immune-therapeutic strategies against NSCLC lung cancer and potentially also against other entities. Our three-pronged approach to achieve this goal is to: (i) delineate biological and clinical properties of the immunological PKC/NR2F6 network, (ii) validate NR2F6 as an immune-oncology combination target needed to overcome limitations to ""first generation anti-PD-1 checkpoint inhibitors"" rendering T cells capable of rejecting tumours and their metastases at distal organs and (iii) exploit human combinatorial T cell therapy concepts for prevention of immune-related adverse events as well as of tumour recurrence by reducing opportunities for the tumour to develop resistance in the clinic. Insight into the functions of NR2F6 pathway and involved mechanisms is a prerequisite for understanding how the microenvironment at the tumour site either supports tumour growth and spread or prevents tumour initiation and progression, the latter by host-protective cancer immunity."

2 484 325 €

Start date: 2018-10-01, End date: 2023-09-30