Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : FAITH (Horizon 2020, appel 2020, Proof of concept grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : German Cancer Research Center — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : DKFZ
Type d'entité : Recherche
Financement ERC de l'entité : 150000.0 €

Changes in life-style and nutrition have increased the incidence of obesity/overweight and metabolic syndrome resulting in a pathology called Non-alcoholic fatty liver disease (NAFLD). Currently, 130 million people in Western countries have NAFLD and this number is constantly increasing. A significant number of patients develop non-alcoholic steatohepatitis (NASH), fibrosis and subsequently liver cancer. At the same time no efficient therapeutics exist to treat NASH or NASH-liver cancer transition. We could demonstrate that infiltration and aggregation of platelets in the liver is the initial and the disease accompanying/maintaining process. Application of a conventional antiplatelet-therapy (APT) prevented or reverted established NASH in mice and men and abandoned subsequent liver cancer development in mouse models. Existing APT bear unwanted side effects and health issues. We identified the platelet-derived surface molecule GPIba as the critical mediator of platelet-derived immune activation, NASH and liver cancer. Using an antibody blocking the thrombin-binding site of GPIba, prevented established NASH, fibrosis and liver cancer without affecting hemostasis (Malehmir et al. 2019 Nature Medicine). The identified novel strategy differentiates itself from all other approaches to treat NASH due to some unique application opportunities: (I) no necessity to change patients’ nutritional habits, resulting in a high acceptance on the patient´s side, (II) no systemic immunosuppression of the patients´ immune system and (III) circumventing unwanted severe side effects of conventional APT by decoupling platelet-derived inflammatory function from platelet-derived aggregation/hemostasis. We intend (1) to produce nanobodies/antibodies that functionally block the human thrombin binding site of GPIba, (2) to confirm the therapeutic activity in preclinical NASH models carrying a humanized GPIba and (3) to lay the ground for necessary subsequent steps towards the market.

Mots-clés : nash,liver cancer,prevention,nanobody,antibody treatment,cancer and its biological basis,metabolism,biological basis of metabolism related disorders,organ physiology and pathophysiology
Projet ERC : MERA (Horizon 2020, appel 2015, Advanced grants)
Domaine scientifique : Life Science
Panel : Molecules of Life: Biological Mechanisms, Structures and Functions
Entité participante : Humboldt-Universität zu Berlin — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : HU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2398750.0 €

Channelrhodopsin, which was discovered and described as a light-gated ion channel in my laboratory, has revolutionized the field of neuroscience over the past decade by enabling researchers to specifically activate selected neurons in a large ensemble of neuronal cells with short light flashes, a technology we now call "Optogenetics." However, though highly desirable, the inactivation of specific cells using moderate or low light intensities is not yet possible. The recently discovered rhodopsin-guanylyl-cyclase (RhGC) of the fungus Blastocladiella emersonii offers an elegant solution to this problem. Moreover, RhGC is a totally novel and uncharacterized sensory photoreceptor, and the first member of an enzyme rhodopsin family that urgently awaits in-depth characterization. Accordingly, the goal of the “mechanism of enzyme rhodopsin activation” (MERA) proposal is to obtain a comprehensive understanding of this novel photoreceptor, and to determine its functionality for broad application in optogenetics and other research fields. The MERA project is subdivided into four objectives. The first objective is the characterization and engineering of RhGC in cell lines and neurons as well as coexpression of RhGC with a cGMP-gated K+ channel to develop a "Light-Hypopolarizer" for cell inactivation. The second objective is to understand the dynamics of RhGC using a variety of biophysical technologies including time resolved UV-vis, FTIR, and Raman and EPR spectroscopy. A third objective is the generation of crystals for X-ray crystallography and the development of a three dimensional RhGC model. The fourth and final objective is the computer-aided conversion of RhGC into a rhodopsin-phosphodiesterase (RhPDE) for down-regulation of the second messenger cGMP and/or cAMP using light. The ultimate outcome will be a detailed understanding of a novel class of sensory photoreceptors with new perspectives for broad optogenetic applications.

Mots-clés : optogenetics,light activated enzymes,infrared spectroscopy
Projet ERC : ATTOLIQ (Horizon 2020, appel 2017, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Physical and analytical chemical sciences
Entité participante : Board of the Swiss Federal Institutes of Technology — Pays : Suisse — Rôle : PI
Acronyme de l'entité : ETH Zurich
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2750000.0 €

Charge and energy transfer are the key steps underlying most chemical reactions and biological transformations. The purely electronic dynamics that control such processes take place on attosecond time scales. A complete understanding of these dynamics on the electronic level therefore calls for new experimental methods with attosecond resolution that are applicable to aqueous environments. We propose to combine the element sensitivity of X-ray spectroscopy with attosecond temporal resolution and ultrathin liquid microjets to study electronic dynamics of relevance to chemical, biological and photovoltaic processes. We will build on our recent achievements in demonstrating femtosecond time-resolved measurements in the water, attosecond pho-toelectron spectroscopy on a liquid microjet and measuring and controlling attosecond charge migration in isolated molecules. We will first concentrate on liquid water to study its electronic dynamics following outer-valence ionization, the formation pathway of the solvated electron and the time scales and intermolecular Coulombic decay following inner-valence or core-level ionization. Second, we will turn to solvated species and measure electronic dynamics and charge migration in solvated molecules, transition-metal complexes and pho-toexcited nanoparticles. These goals will be achieved by developing several innovative experimental tech-niques. We will develop a source of isolated attosecond pulses covering the water window (285-538 eV) and combine it with a flat liquid microjet to realize attosecond transient absorption in liquids. We will complement these measurements with attosecond X-ray emission spectroscopy, Auger spectroscopy and a novel hetero-dyne-detected variant of resonant inelastic Raman scattering, exploiting the large bandwidth that is naturally available from attosecond X-ray sources.

Mots-clés : attosecond spectroscopy,x ray spectroscopy,liquid microjets,electronic dynamics,charge migration,intermolecular coulombic decay,transient absorption spectroscopy
Projet ERC : SOFTCHARGE (Horizon 2020, appel 2015, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Physical and analytical chemical sciences
Entité participante : University of London — Pays : Royaume-Uni — Rôle : PI
Acronyme de l'entité : U. London
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1989988.0 €

Charge transport (CT) in soft condensed matter is at the heart of many exciting and potentially revolutionising technologies ranging from organic photovoltaic cells to nanobioelectronic transistors. Tremendous progress has been made on these research frontiers over the last twenty years. Yet, our fundamental understanding of CT in organic and biological semiconductors (OBS) that could rationalise experimental observations and guide further advances in the field is still very limited. These materials are characterised by strong, anharmonic thermal fluctuations and small energy barriers for CT, which renders standard theories such as band theory or activated electron hopping in many cases entirely inadequate. Here, I propose the development of a disruptive computational method‚ based on non-adiabatic molecular dynamics (NAMD), that will open the door for ground-breaking new insight into this problem. The method will be able to access length and time scales that are presently unreachable with existing NAMD methods through an ultrafast yet error-controlled estimation of Hamiltonian matrix elements and derivatives. Applications will focus on (1) ultrapure single crystalline organic semiconductors (OS) to help uncover the true nature of charge carriers and their transport mechanism (2) structurally heterogeneous OS containing crystalline/amorphous interfaces to establish structure-charge mobility relationships (3) Ti-modified OS to aid the design of high dielectric-high mobility hybrid inorganic/organic semiconducting materials for next-generation photovoltaic devices (4) bacterial nanowire proteins to support the development of future bionanoelectronic devices. The work will (i) result in a user-friendly open software tool freely available for the scientific community (ii) yield important guidelines informing the development of high-performance OBS materials that have the potential to transform emerging technologies of the 21st century.

Mots-clés : electron transfer,molecular dynamics,density functional theory,non adiabatic dynamics,organic semiconductors,redox proteins
Projet ERC : MolStrucDyn (Horizon 2020, appel 2016, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Physical and analytical chemical sciences
Entité participante : University of Gothenburg — Pays : Suède — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2000000.0 €

Chemical reactions in solution are strongly influenced by femtosecond solvent-solute dynamics. Likewise, proteins provide specific environments to control the outcome of substrate reactions. The molecular understanding of these effect are currently poorly developed. I propose to fill this knowledge gap by ‘filming’ elementary chemical reactions in solution and in proteins. I will pioneer new time-resolved scattering and diffraction experiments using X-ray Free Electron Lasers (XFELs). Using femtosecond time-resolved X-ray scattering, I plan to decipher the structural dynamics of bond breaking and bond formation in iodine containing compounds in solution. I will pioneer time-resolved fluctuation correlation X-ray scattering to recover full electron density maps of the reaction trajectories at an atomic resolution. I will visualize the as yet unknown structures of reaction intermediates and the solvent response. Furthermore, I propose to investigate the molecular photoresponse of phytochrome photoconversion with femtosecond time-resolved serial microcrystallography. Phytochromes are ubiquitous photosensory proteins in plants and are essential to all vegetation on earth. I will resolve how the chromophore and the protein react collectively to photoexcitation and how this leads to conformational changes. Combined, this interdisciplinary project will yield microscopic understanding on how the surrounding of reactants guides the outcome of elementary (bio)chemical reactions. This program builds on my strengths in structural biology of phytochromes (Takala et al., Nature, 2014), time-resolved X-ray scattering (Westenhoff et al., Nature Methods 2010), and femtosecond spectroscopy (21 papers in PRL, JACS, Nature Methods 2006-2012 & 2016). The new XFEL-based methods will have wide-ranging applications in chemistry and biology. My work will open new horizons in physical chemistry and structural biology.
Projet ERC : ECHO-GRACADE (Horizon 2020, appel 2019, Advanced grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Synthetic Chemistry and Materials
Entité participante : University of Girona — Pays : Espagne — Rôle : PI
Acronyme de l'entité : UdG
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2499387.5 €

Chemo- and enantioselective oxidation of aliphatic C-H bonds is a cornerstone reaction in metabolism. The ubiquitous presence of multiple and diverse C-H bonds in organic molecules is used by oxidative enzymes to deliver functionality and chirality to metabolite precursors, rapidly creating product diversity. Despite its huge potential in organic synthesis, non-enzymatic enantioselective C-H oxidation of aliphatic sites remains inaccessible and has never been incorporated in synthesis. Harnessing the power of this reaction will open straightforward, yet currently inaccessible, paths in synthetic planning. However, realization of this goal requires conceptual breakthroughs in order to chemo-, regio- and stereo-selectively create a C-O bond from a non-activated alkyl C-H bond, even in the presence of a priori more reactive groups. In this project, chemo-, and site-selective asymmetric aliphatic oxidation is targeted by taking advantage of; a) stereoretentive enzyme-like metal-based C-H oxidations performed by small molecule manganese catalysts, devised as minimalistic hydroxylases, and b) polarity reversal exerted by fluorinated alcohol solvents in electron-rich functional groups, which enable chemoselective C-H hydroxylation of densely functionalized molecules. Desymmetrization via enantioselective C-H oxidation is devised as a powerful type of reaction that will create multiple chiral centers in a single step. Building on the rich chemical diversity and modular architecture of aminopyridine manganese complexes, rapid elaboration of libraries of catalysts is targeted. Rational manipulation of steric, electronic, directing effects and supramolecular substrate recognition factors guided by multiple parametrization analyses will be employed for directing evolution in catalyst design. This project will provide the catalysts and their use in paradigmatic reactions in order to establish enantioselective C-H oxidation as a reliable tool in organic synthesis.

Mots-clés : asymmetric catalysis,selective c h oxidation,metal catalyzed reactions,high valent manganese oxo,hydrogen atom transfer,polarity reversal,remote desymmetrization,multivariate regression analyses,catalyst design
Projet ERC : CfC (Horizon 2020, appel 2017, Proof of concept grants)
Entité participante : Board of the Swiss Federal Institutes of Technology — Pays : Suisse — Rôle : PI
Acronyme de l'entité : ETH Zurich
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 150000.0 €

Chemotherapy, often given in conjunction with other therapies is infamous for its off target associated side effects. Recent studies have shown that drugs combinations can act synergistically at certain ratios and are more effective and less toxic than single drug therapies. Despite promising in vitro results, combination drug therapy for Oncology has not been successfully translated to the clinic due to lack of efficient delivery systems that can maintain the desired synergistic drug concentrations in the body as each drug has a different pharmacokinetics and toxicity profile. The objective of this project is to develop a universal platform for simultaneous delivery of multiple drugs to specific cells in vivo using a protein cage that was developed in our laboratory for encapsulation of diverse cargoes.

Mots-clés : protein cage,protein design,drug delivery,protein therapeutics,cancer therapy,combination chemotherapy
Projet ERC : DIGIPARENT (Horizon 2020, appel 2020, Advanced grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : University of Turku — Pays : Finlande — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2499198.0 €

Childhood disruptive behavior problems pose huge challenge to societies given the high lifetime burden and costs associated. Mounting evidence shows that parent training is the most effective psychosocial treatment for these problems. However, most parents in need of such training do not receive it. DIGIPARENT shift the research focus from specialized care face-to-face parent training to study digitally assisted parent training interventions when implemented in primary health. The proposal is divided into four Work Packages (WP): WP1 is the first population based study about the long-term outcomes and modifiers of digitally assisted parent training. It addresses what works and how it works in real-world practice. WP2 will yield novel knowledge on the genetic and epigenetic variants associated with childhood disruptive behavior and the epigenetic response to childhood psychosocial interventions. WP 3 shifts the research focus from a manualized one-size-fits-all parent training intervention approaches to one that is personalized for families by artificial intelligence and machine learning algorithms. WP 4 adopts a novel approach by comparing community level, well-being indicators when different combinations of digital and face-to-face parent training strategies are implemented in “real world”. DIGIPARENT combines an evidence-based approach to child mental health with the latest technology and offers the potential for scientific breakthroughs, including the use of artificial technology to produce digital content tailored to the needs of individual families. Detection of genetic factors related to treatment response and possible epigenetic outcomes of treatments opens avenues for new scientific questions on how treatments can affect human biology. DIGIPARENT responds to the urgent need to study digital and remote interventions as child mental health services struggle with the considerable increase in demand for services due to the COVID-19 pandemic

Mots-clés : digital interventions,children,disruptive behavior,parenting,family health,mental health,early prevention,implementation
Projet ERC : DEVCOM (Horizon 2020, appel 2019, Starting grants)
Domaine scientifique : Social Sciences and Humanities
Panel : The Human Mind and Its Complexity
Entité participante : University of the Basque Country — Pays : Espagne — Rôle : Partner
Acronyme de l'entité : UPV;EHU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 14489.0 €

Children are born communicators. A growing body of developmental evidence suggests that the cognitive abilities enabling the expression and comprehension of communicative intentions – so-called pragmatic abilities – which underlie language use and understanding, develop early. However, a puzzling feature of pragmatic development is young children’s difficulties with non-literal uses of language (e.g., “I love you so much I could eat you up!”). How can children be early experts at a range of pragmatically complex tasks requiring attention to speakers’ intentions, but act like ‘literal listeners’ in other contexts? The objective of DEVCOM is to provide an account of the stages and factors involved in children’s developing competence with non-literal uses of language. The project will investigate the novel hypothesis that children’s growing sensitivity to sense conventions, which determine the publicly accepted meaning of words in their language, impedes children’s pragmatic reasoning with non-literal uses in the pre-school years. The empirical data will be gleaned from experimental studies with typically developing children aged 2-7 years, focusing on lexical innovation, lexical modulation, and figurative language, each highlighting the interaction of pragmatic reasoning with sensitivity to sense conventions in a distinct way. Further, the project will investigate whether the persistent difficulties with non-literal uses faced by children with Autism Spectrum Disorder may be linked to the same source. The project will use a set of novel methodologies combining explicit and implicit measures, assuming that while children’s performance on explicit measures is liable to be affected by a growing sensitivity to sense conventions, implicit measures may be more revealing of their actual pragmatic abilities. The empirical results will provide input to a novel theoretical account of pragmatic development that resolves the developmental puzzle of non-literal uses of language.

Mots-clés : pragmatic development,lexical pragmatics,developmental psychology,sense conventions,non literal uses of language,philosophy of language,atypical pragmatic development,language acquisition
Projet ERC : EMBRYOandLATERHEALTH (Horizon 2020, appel 2014, Consolidator grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : Erasmus MC — Pays : Pays-Bas — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1969586.04 €

Children born preterm or with a small size at birth have increased risks of cardiovascular disease and type 2 diabetes in adulthood. These intriguing associations strongly suggest that common diseases have at least part of their origins in early fetal life. From both an etiological and preventive perspective, it is important to disentangle the early fetal critical periods and causal pathways. An accumulating body of evidence suggests that early pregnancy, or even the preconception period, may influence the risk of cardiovascular and metabolic disease throughout the lifecourse. The main hypothesis for this project is that adverse exposures before or very early in pregnancy induce embryonic and placental developmental adaptations, which permanently affect cardiovascular and metabolic development and predispose individuals to both adverse outcomes at birth and cardiovascular and metabolic dysfunction and diseases in later life. I will use an integrated epidemiological, molecular and clinical full lifecourse approach from preconception to adulthood embedded in three population-based cohort studies. Innovative element are: 1) focus on developmental adaptations during the embryonic phase and early placentation assessed by advanced imaging studies at 6, 8, 10 and 12 weeks of gestation; (2) detailed cardiovascular and metabolic studies in infancy and late childhood, including 3T MRI of the heart, aorta, liver and abdomen, metabolomics analyses; and (3) genome-wide DNA-methylation studies to identify specific DNA-methylation changes related to preconception or early pregnancy exposures, which persist in late childhood and adulthood and are associated with cardiovascular and metabolic outcomes in later life. With these approaches, this project will provide unique and important new perspectives into the earliest origins of cardiovascular disease and type 2 diabetes and will ultimately contribute to development of preventive strategies focused on future parents and children.