Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : MetaboSENS (Horizon 2020, appel 2018, Consolidator grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Institut national de la santé et de la recherche médicale — Pays : France — Rôle : PI
Acronyme de l'entité : Inserm
Type d'entité : Recherche
Financement ERC de l'entité : 1999391.0 €

Nutrient sensing enables metabolic homeostasis by matching energy use with fuel availability. The vast body of knowledge on pro-anabolic nutrient sensors, such as insulin and class 1 phosphoinositol-3 kinase (PI3K) signalling exposed the missing links in molecular coordination of catabolism. The cellular catabolism relies on mitochondrial activities and on lysosomal pathway of autophagy, both paced by the biological clock. However, how pro-catabolic nutrient sensors synchronize these catabolic activities is not well understood. We discovered that class 3 PI3K, the only PI3K present in all eukaryotes, is essential for catabolic homeostasis in vivo, but the mechanisms of its metabolic functions are still lacking. We found novel roles for class 3 PI3K in metabolic adaptation to fasting and mitochondrial activity, beyond its established functions in autophagy and endosomal trafficking. These findings form the basis of our innovative interdisciplinary research program that will investigate the molecular bases of Metabolic integration in vivo by a nutrient SENSing pathway of class 3 PI3K (MetaboSENS). In the MetaboSENS research program, we seek to identify transcription factor networks and regulatory complexes of class 3 PI3K that serve its catabolic integrator function. We aim to reveal the physiological oscillation of class 3 PI3K signalling and its reciprocal impact on metabolic timekeeping. Finally, the MetaboSENS project will combine patient analyses and the medical expertise of my team to reveal, for the first time, genetic alterations in class 3 PI3K signalling in inborn metabolic disease. The new mechanisms that we discover may provide therapeutic targets that we will test in the pre-clinical models. Altogether, the MetaboSENS project will redefine our view of systemic catabolism.

Mots-clés : nutrient sensing,catabolism,class 3 phosphoinositide 3 kinase,vps15,vps34,circadian clock,nuclear receptor transcription factors,mitochondria,lysosome,autophagy,human rare liver disease
Projet ERC : aCROBAT (Horizon 2020, appel 2014, Starting grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : University of Copenhagen — Pays : Danemark — Rôle : PI
Acronyme de l'entité : UCPH
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1497007.51 €

Obesity and diabetes have reached pandemic proportions and new therapeutic strategies are critically needed. Brown adipose tissue (BAT), a major source of heat production, possesses significant energy-dissipating capacity and therefore represents a promising target to use in combating these diseases. Recently, I discovered a novel link between circadian rhythm and thermogenic stress in the control of the conserved, calorie-burning functions of BAT. Circadian and thermogenic signaling to BAT incorporates blood-borne hormonal and nutrient cues with direct neuronal input. Yet how these responses coordinately shape BAT energy-expending potential through the regulation of cell surface receptors, metabolic enzymes, and transcriptional effectors is still not understood. My primary goal is to investigate this previously unappreciated network of crosstalk that allows mammals to effectively orchestrate daily rhythms in BAT metabolism, while maintaining their ability to adapt to abrupt changes in energy demand. My group will address this question using gain and loss-of-function in vitro and in vivo studies, newly-generated mouse models, customized physiological phenotyping, and cutting-edge advances in next generation RNA sequencing and mass spectrometry. Preliminary, small-scale validations of our methodologies have already yielded a number of novel candidates that may drive key facets of BAT metabolism. Additionally, we will extend our circadian and thermogenic studies into humans to evaluate the translational potential. Our results will advance the fundamental understanding of how daily oscillations in bioenergetic networks establish a framework for the anticipation of and adaptation to environmental challenges. Importantly, we expect that these mechanistic insights will reveal pharmacological targets through which we can unlock evolutionary constraints and harness the energy-expending potential of BAT for the prevention and treatment of obesity and diabetes.

Mots-clés : circadian rhythm,brown adipose tissue,energy expenditure,diabetes,obesity
Projet ERC : The MATRIX (Horizon 2020, appel 2018, Starting grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Aarhus University — Pays : Danemark — Rôle : PI
Acronyme de l'entité : AU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1657123.03 €

Obesity and its affiliated metabolic diseases pose serious public-health challenges. However, certain patient subgroups appear protected. To halt the socio-economic burden of metabolic disease, we urgently need to understand what distinguishes the Metabolically-Healthy-Lean (MHL), Metabolically-Unhealthy-Lean (MUL), Metabolically-Healthy-Obese (MHO) and Metabolically-Unhealthy-Obese (MUO) phenotypes, and which factors promote metabolic health. Inflammation has been proposed as a target, as it is a key driver of metabolic disease. However, clinical trials show limited evidence that anti-inflammatory drugs reduce diabetes. Why is that? Inflammation consists of a pro-inflammatory phase followed by a pro-resolving phase, which are regulated by different cells/pathways. This is critical to consider when attempting a therapeutic approach. Based on my preliminary data, I hypothesise that what separates MHL/MHO from MUL/MUO are not pro-inflammatory triggers, but rather the endogenous ability of individuals to resolve inflammation. Adipose extracellular-matrix remodelling appears critical, and pro-resolving lipids promote a MUO-to-MHO switch. My overall goal is to determine molecular pathways that differentiate the MHL/MUL/MHO/MUO phenotypes (Aim 1-4), and to investigate the therapeutic potential of pro-resolving lipids (Aim 5). This multi-disciplinary project combines cutting-edge techniques with state-of-the-art translational approaches. Through my unique access to human biobanks, I will generate patient-specific cell-lines and test drug-targets ex vivo. Novel bioinformatics pipelines will produce protein/lipid/metabolite fingerprints associated with respective patient groups, ultimately providing a new approach to tackle obesity-related comorbidities. My experience in the specialised field of pro-resolving lipid biology, coupled with my lab’s unique placement at a translational site, makes me the right candidate to lead this research program.

Mots-clés : obesity,metabolic health,inflammation,inflammatory resolution,specialized pro resolving lipid mediators,lipoxin
Projet ERC : Yoyo-LepReSens (Horizon 2020, appel 2020, Consolidator grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Helmholtz Zentrum München — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : HMGU
Type d'entité : Recherche
Financement ERC de l'entité : 1999976.0 €

Obesity and its comorbid sequelae are major health burdens across European nations. Many citizens would greatly benefit from permanent weight loss, but only a few succeed. They rather suffer from weight regain after dieting, often referred to as Yoyo effect. Delineating the largely unexplored, CNS-driven molecular events that impede sustainable weight loss and drive the Yoyo effect is a prerequisite for future therapies, and a major goal of my proposal. Recently, my lab demonstrated unprecedented weight loss in diet-induced obese mice treated with the plant-derived leptin sensitizer celastrol. Our data suggested breakthrough potential for therapeutic anti-obesity strategies built upon leptin re-sensitization, and pointed towards a key role for orexigenic circuitry and AgRP neurons residing in the hypothalamic arcuate nucleus. As 1st objective, we will 1) establish if leptin resistance originates in AgRP neurons, 2) delineate the molecular underpinnings of leptin resistance and leptin resensitization in AgRP neurons, 3) verify novel drug-able leptin signalling components in murine and human iPSC-derived cells and 4) identify leptin sensitizing weight loss drugs. AgRP neurons will also be in the focus of my 2nd objective that targets epigenetic mechanisms of Yoyo dieting. Building upon our own data on epigenetic mechanisms that drive weight re-gain through hyperphagia, we will 1) establish if an epigenetic memory for obesity in AgRP neurons exists, 2) explore by Crispr-Cas9-based trans-epigenetic modulation of AgRP neurons in mice whether resetting the epigenetic memory for obesity can prevent weight regain and 3) demonstrate the human relevance of our new weight regulatory genes in post-mortem human hypothalami of lean, obese or type 2 diabetic donors. Overall, my proposal will establish hypothalamic AgRP neurons as crucial drivers for leptin resistance and Yoyo dieting. My translational aims are further providing the groundwork for future anti-obesity therapeutics.

Mots-clés : obesity,weight loss,yoyo dieting,epigenetics,hypothalamus,agrp,leptin
Projet ERC : METHID (Horizon 2020, appel 2015, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Earth system science
Entité participante : Imperial College London — Pays : Royaume-Uni — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1500000.0 €

Observation and Modelling of Radiocarbon in Atmospheric Methane for Methane Source Identification Greenhouse gas emissions are the primary cause of global climate change, and methane (CH4) is the second most important contributor after carbon dioxide (CO2). Major sources of methane are both natural (wetlands) and anthropogenic (agriculture, landfills and fossil fuels). Current efforts to assess the anthropogenic CH4 influence on climate change and the effectiveness of mitigation policies for CH4 are limited by large uncertainties in estimates of total methane emissions and their attribution to various sources by accounting-based techniques. This project will pioneer and apply innovative techniques for atmospheric observation and modelling of radiocarbon in CH4 that will enable unique quantification of fossil fuel vs. biogenic CH4 sources at regional and global scales, thereby improving the estimation and attribution of CH4 emissions of different types. The proposed work will significantly advance the frontier of current research on atmospheric methane and the characterization of anthropogenic sources on policy-relevant scales, and it has the potential to influence climate policy and industrial practices over the next 10-20 years.
Projet ERC : ODDSUPER (Horizon 2020, appel 2017, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Condensed matter physics
Entité participante : Uppsala University — Pays : Suède — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1121660.0 €

Odd-frequency superconductivity is a very unique superconducting state that is odd in time or, equivalently, frequency, which is opposite to the ordinary behavior of superconductivity. It has been realized to be the absolute key to understand the surprising physics of superconductor-ferromagnet (SF) structures and has also enabled the whole emerging field of superconducting spintronics. This project will discover and explore entirely new mechanisms and materials for odd-frequency superconductivity, to both generate a much deeper understanding of superconductivity and open for entirely new functionalities. Importantly, it will generalize and apply my initial discoveries of two new odd-frequency mechanisms, present in bulk multiband superconductors and in hybrid structures between topological insulators and conventional superconductors, respectively. In both cases odd-frequency superconductivity is generated without any need for ferromagnets or interfaces, completely different from the situation in SF structures. The result will be a significant expansion of the concept and importance of odd-frequency superconductivity to a very wide class of materials, ranging from multiband, bilayer, and nanoscale superconductors to topological superconductors. The project will also establish the connection between topology and odd-frequency pairing, which needs to be addressed in order to understand topological superconductors, as well as incorporate new materials and functionality into traditional SF structures. To achieve these goals the project will develop a novel methodological framework for large-scale and fully quantum mechanical studies with atomic level resolution, solving self-consistently for the superconducting state and incorporating quantum transport calculations.

Mots-clés : odd frequency superconductivity,proximity induced superconductivity,multiband superconductors,topological states of matter,superconducting hybrid structures
Projet ERC : sociOlfa (Horizon 2020, appel 2019, Starting grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : Centre national de la recherche scientifique — Pays : France — Rôle : PI
Acronyme de l'entité : CNRS
Type d'entité : Recherche
Financement ERC de l'entité : 1498875.0 €

Olfaction is a central sensory modality in most Mammals as it supports vital functions such as feeding, mating and social interactions. Social chemosignals (olfactory cues from urine or body secretions) are efficient communication cues carrying important information such as territory ownership, resources’ locations and identity. Remembering such information is a key advantage for individuals allowing them to adapt their behaviors based on prior experience. However, how social chemosignals are processed and stored in the brain for future recall is still unclear. This project aims at identifying the brain-wide mechanisms underlying the contribution of social chemosignals to spatial and social memory in the mouse. The hippocampus is a key brain region for these two fundamental memory functions and it shares direct anatomical connections with the olfactory system that processes social odors. Using advanced computational methods and cutting-edge technologies that enable recording and manipulating large neuronal ensembles in freely moving mice, we will: - shed light on the mechanisms of spatial memory consolidation: we hypothesize that a dialog between the olfactory cortex and the hippocampus during sleep underlies the memory of an environment marked by social scents. - track the brain substrates of individuals’ identity in mice and their dependence on olfactory inputs: we hypothesize that during social learning, the response of neuronal circuits (1) reflects the unique olfactory signature of the encountered individual, and that (2) it changes as this individual becomes familiar. - test whether a coordination between olfactory and memory networks is essential to the formation of social recognition memory. Overall, this project will provide important insights on the network mechanisms of memory function and will contribute to our understanding of social behaviors.

Mots-clés : olfaction,social recognition,identity,memory,oscillations,spatial memory,consolidation,sleep,sharp wave ripples,hippocampus,piriform,lateral entorhinal cortex,population coding,electrophysiology,optogenetics
Projet ERC : EPIScOPE (Horizon 2020, appel 2015, Consolidator grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : Karolinska Institutet — Pays : Suède — Rôle : PI
Acronyme de l'entité : KI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1895155.0 €

Oligodendrocytes (OL) are glial cells that mediate myelination of neurons, a process that is defective in multiple sclerosis (MS). Although OL precursor cells (OPCs) can initially promote remyelination in MS, this regenerative mechanism eventually fails in progressive MS. OPCs go through several epigenetic states that ultimately define their potential to differentiate and myelinate. OPCs in progressive MS stall in a distinct epigenetic state, incompatible with differentiation and remyelination. We hypothesize that these OPCs regress to an epigenetic state reminiscent of the state of embryonic OPCs, which remain undifferentiated. In this proposal, we aim to uncover the causes behind the remyelination failure upon disease progression in MS. We will determine the epigenetic/transcriptional states of OPCs during development and in MS, using single cell and bulk RNA sequencing and quantitative proteomics. We will further investigate how the interplay between transcription factors (TFs), chromatin modifiers (ChMs) and non-coding RNAs (ncRNAs) contributes to the transition between epigenetic states of OPCs. The results will allow the identification of ChMs and ncRNAs that can modulate these states and thereby control OPC differentiation and myelination. We will use this knowledge to investigate whether we can reverse the epigenetic state of OPCs in MS, in order to promote their differentiation and remyelination. The unique combination of leading-edge techniques such as SILAC coupled with immunoprecipitation and mass-spectrometry, single-cell RNA sequencing, ChIP-Sequencing, among others, will allow us to provide insights into novel epigenetic mechanisms that might be underlying the effects of environmental and lifestyle risk factors for MS. Moreover, this project has the potential to lead to the discovery of new targets for epigenetic-based therapies for MS, which could provide major opportunities for improved clinical outcome of MS patients in the near future.

Mots-clés : epigenetics,non coding rnas,chromatin,oligodendrocyte development,myelin,multiple sclerosis
Projet ERC : MITOvTOXO (Horizon 2020, appel 2019, Starting grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : Max Planck Society — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : MPG
Type d'entité : Recherche
Financement ERC de l'entité : 1500000.0 €

Once a pathogen has eluded immune defences to establish a replicative niche in the cytosol, it requires nutrients to grow—the same nutrients that host organelles need for their biogenesis and to perform cellular metabolic processes. The microbe must therefore compete with organelles for these nutrients.. This organelle-microbe competition for metabolites is a fundamental, but little understood aspect of the host–pathogen interaction. I recently defined one example of this competition, between mitochondria and the human parasite Toxoplasma gondii. During infection, Toxoplasma exploits host lipophagy to gain access to cellular fatty acids essential for its growth. To counter this, host mitochondria fuse to enhance fatty acid uptake, limiting Toxoplasma access to a key host resource and thus restricting its growth. This work shows that mitochondria—essentially domesticated parasites—metabolically defend the cell during infection, and opens several key questions that I will address in this proposal, including: a) by what mechanism do mitochondria enhance fatty acid oxidation to defend the cell against fatty acid siphoning by microbes?; b) can mitochondrial fatty acid oxidation be exploited to restrict microbial growth in vivo?; and c) do mitochondria play a broader role in cellular defence by sequestering other essential metabolites from microbes? The answers to these questions will lead to a deeper understanding of the role of mitochondria in the cellular response to microbes, and begin to address our long-term goal of understanding how human metabolism influences the progression of infectious disease. The innovative approaches I describe here are broadly applicable to dissecting the metabolic interactions between other organelles and diverse infectious agents.

Mots-clés : mitochondria,parasites,toxoplasma gondii,nutrient competition,cholesterol,host pathogen,fatty acid,mitochondrial fusion,anti microbial therapy,cellular defense
Projet ERC : ITHACA (Horizon 2020, appel 2017, Proof of concept grants)
Entité participante : Istituti di Ricovero e Cura a Carattere Scientifico — Pays : Italie — Rôle : PI
Acronyme de l'entité : IRCCS
Type d'entité : Organismes privés (hors enseignement)
Financement ERC de l'entité : 150000.0 €

One main objective of our ERC Advanced Grant project (InMec, No 341131) was to determine how cancer stem cells (CSCs) contribute to tumour growth, and the relative impact of quiescent versus proliferative CSCs. In Acute Myeloid Leukaemia (AML), our results strongly suggest that quiescent leukaemia stem cells are critical for leukaemia maintenance and relapse after treatments. AML is an aggressive and frequently fatal hematologic malignancy. It is usually sensitive to chemotherapy at its onset, leading to disease remission in most patients; however, the majority of patient will later relapse and eventually die. Notably, leukaemia stem cells are often resistant to chemotherapy. We will use our innovative phage-display antibody screening platform to generate antibodies against AMLs. The screening will be performed directly on human AMLs growing in vivo, using an innovative mouse xenotransplantation model followed by an NGS-based antibody selection procedure. We plan to isolate antibodies that selectively recognize leukaemia stem cells, either quiescent or proliferating. Our primary goal is to develop novel therapeutic antibodies for the treatment of AMLs. This project will also indirectly confirm the hypothesis that leukaemia stem cells are the real fuel of the disease. We expect that this project will lead to quick and cheap identification, cloning and validation of human recombinant antibodies towards against AML leukemic stem cells. The use of phage display technology to isolate leukemic stem cell-specific human recombinant antibodies is to our knowledge unprecedented. The development of candidate antibodies against AMLs will be accompanied by the promotion of commercial/exploitation activities such as market and competition analyses, intellectual property management, and product and business development through the activities of our partner TTFactor.

Mots-clés : acute myeloid leukemia,therapeutic antibodies,in vivo phage display screening,leukemic stem cells