Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : SENTINEL (Horizon 2020, appel 2014, Advanced grants)
Domaine scientifique : Life Science
Panel : Immunity, Infection and Immunotherapy
Entité participante : Amsterdam University Medical Centers — Pays : Pays-Bas — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2499156.0 €

HIV-1 is a major global health problem with over 2 million new infections every year, and although antiretroviral therapy is effective, chronic infected patients suffer from severe co-morbidities due to immune dysfunction. With the proposed SENTINEL project, I aim to identify novel strategies to enhance innate antiviral immunity to HIV-1 to limit establishment and progression of chronic disease. Our novel data strongly suggest that induction of antiviral innate immune responses in dendritic cell subsets delays disease progression and improves survival in chronic HIV-1-infected patients. Current paradigm suggests that HIV-1 evades innate sensing in dendritic cells and that this underlies immune dysfunction. However, our innovative data demonstrate that HIV-1 actively suppresses a novel innate sensing mechanism and antagonizing this HIV-1 suppression by drugs strongly enhanced antiviral immunity. Strikingly, we identified a gene polymorphism in a component of the novel HIV-1 sensing machinery, rendering the pathway insensitive to HIV-1 suppression; this polymorphism is associated with delayed disease progression and improved survival in HIV-1 patients from the Amsterdam Cohort Studies. Thus, I hypothesize that therapies counteracting the suppression by HIV-1 will enhance antiviral immunity and restore immune dysfunction in chronic patients. Within this SENTINEL project, novel targets for HIV-1 therapy will be identified. As we identified proto-oncogenes involved in the suppression of innate immune responses by HIV-1, we will also screen clinically approved anti-cancer drugs as novel therapies to enhance the innate immune responses to HIV-1. Our exciting data strongly underscore the innovation and feasibility of the project. The unique expertise of my group in elucidating complex mechanisms that shape immunity, our innovative ex vivo human tissue infection models and cohort studies will be crucial in the proposed research and paramount to its success.

Mots-clés : hiv 1,dendritic cell,pattern recognition receptor,adaptive immunity
Projet ERC : OnTarget (Horizon 2020, appel 2019, Consolidator grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : Weizmann Institute of Science — Pays : Israël — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2000000.0 €

Half of eukaryotic proteins require targeting to specific organelles to execute their function. Research from multiple labs, including our own, has uncovered some of the pathways that recognize such cargo proteins and target them in an efficient and regulated fashion. However, many central pathways are clearly still missing. Importantly, current studies tend to focus on single cargo proteins and how they utilize one particular targeting pathway, creating an over-simplified view of the cellular road map. In the cell, multiple pathways provide overlapping or competing targeting options for thousands of cargo. Hence, various mechanisms exist to ensure robust but flexible sorting according to cellular needs. Naturally, a big challenge in the field is to understand how this complex network of targeting pathways is coordinated in a live cell during changing conditions. The new tools and approaches that we will create during OnTarget will put us finally in the position to study the whole cellular targeting network and the interplay between its components. Specifically, we will uncover missing targeting pathways (Aim 1); develop techniques to map cargo range for targeting pathways in various environments (Aim 2); and develop an in-cellulo competition assay to define the rules that prioritize the delivery of one cargo over another across conditions (Aim 3). By creating cutting-edge systematic tools that track targeting in live cells as well as by comparing and contrasting multiple pathways and destinations, we will define the rules governing optimal wiring of the targeting network, allowing us to gain a comprehensive view of this process in a cellular context. Our work will unlock the door to full control over protein localization for basic research, as well as for medicine and industry. More broadly, the methodologies that we develop here will provide a platform for addressing any complex biological process that revolves around multiple, overlapping and competing, pathways

Mots-clés : protein targeting,yeast,systematic cell biology,high content screening,peroxisomes,mitochondria,endoplasmic reticulum
Projet ERC : HALODRUGSYN (Horizon 2020, appel 2016, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Synthetic Chemistry and Materials
Entité participante : Ludwig-Maximilians-Universität München — Pays : Allemagne — Rôle : Partner
Acronyme de l'entité : LMU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 70677.5 €

Halogenated arenes and heteroarenes have become essential structural motifs of the pharmaceutical industry to create novel drugs against bacterial infections and cancer, and constitute highly valuable functional units in chemistry. Current methods for the installation of carbon-halogen bonds lack efficiency, selectivity, and practicability within the complex molecular setting of drug development processes. These restrictions prevent many potential drugs from being synthesized in a time- and cost-efficient manner. In this project, I aim to address these challenges by engineering a highly elaborated synthetic toolbox that is equipped with novel transformations of unprecedented efficiency, selectivity and practicability. I will apply these transformations to the construction of novel antibiotics against resistant strains and more efficient chemotherapeutics to combat cancer. The first objective is to establish innovative transformations that enable for the first time an efficient access to halogenated arenes. I will accomplish this goal by developing novel ring-expansion reactions and apply them to the first synthesis of the antibiotic salimabromide in order to address the acute problem of antibiotic resistance. Within the second part of this project, I will extend this unique synthetic platform to heteroarenes and establish a groundbreaking method based on carbon-fluorine bond activation. This will represent the first broadly applicable strategy to produce novel fluorinated heteroarene based anti-cancer drugs with unparalleled precision, efficiency and selectivity. Taken together, the realization of these strategies, all of which are unprecedented, provides for the first time a solution for the limitations associated with current methods. With my expertise in synthetic chemistry, which I have gained from my achievements in natural product synthesis, and an outstanding publication record in this research field, I am confident to accomplish these ambitious goals.

Mots-clés : natural products,total synthesis,halogenated molecules,ring expansion,fluorine chemistry,methodology
Projet ERC : AWAR (Horizon 2020, appel 2020, Starting grants)
Domaine scientifique : Social Sciences and Humanities
Panel : Institutions, Governance and Legal Systems
Entité participante : Peace Research Institute Oslo — Pays : Norvège — Rôle : PI
Acronyme de l'entité : PRIO
Type d'entité : Recherche
Financement ERC de l'entité : 1499628.0 €

Have humans evolved psychological adaptations to war? This question has generated major scientific debate involving anthropologists, archaeologists, economists, primatologists, psychologists, and political scientists. It has shaped popular perceptions of human nature and influenced the views of political leaders. Observing the limits of archaeological, ethnographic, and comparative evidence, I posit that only evidence of special design, obtained from an integrated program of psychological experiments, can conclusively answer this fundamental question. If humans are adapted to war, then human psychology must be equipped with specialized adaptations designed for the effective navigation of war: planning, executing, and defending against coalitional attacks. AWAR probes the existence of such adaptations. It focuses, specifically, on coalitional formidability assessment mechanisms, which likely helped ancestral humans to avoid costly fights. Such mechanisms, if revealed, likely constitute “smoking-gun” evidence that war shaped human evolution. AWAR also explores real-world implications of coalitional formidability assessment mechanisms: if they indeed exist, do they shape our attitudes and behavior today, particularly in the context of modern political violence (e.g., violent anti-government protests and armed civil conflicts)? AWAR presents the first elaborate information-processing model of a coalitional formidability assessment mechanism. In turn, it conducts an integrated program of 20 lab experiments and surveys in 40 countries. Crucially, AWAR holds the potential to reveal the existence of a psychological adaptation in humans, contributing to the growing efforts to map the universal architecture of the human mind. The project’s results will likely appear in major multidisciplinary journals, advancing scholarly debates in at least six disciplines. Most importantly, AWAR breaks new ground for a novel perspective in the study of modern domestic political violence.

Mots-clés : coalitional aggression,evolved adaptations,psychological mechanisms,human evolution,political violence
Projet ERC : aNtHESIS (Horizon 2020, appel 2014, Proof of concept grants)
Entité participante : Weizmann Institute of Science — Pays : Israël — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 150000.0 €

Heart disease and particularly myocardial infarction, i.e. heart attack, is the leading cause of death in the Western world today. The diminished regenerative potential of the heart begins shortly after birth, when most CardioMyocytes (CMs) cease to proliferate and make a transition from hyperplastic to hypertrophic growth. The Tzahor lab has been intensively exploring novel molecules, compounds as well as the molecular mechanisms that facilitate CM cell division in the adult heart of mammals as a strategy for eliciting heart regeneration. These efforts, had led to the identification of novel compounds which significantly increased the proliferation of adult CMs. Drawing upon these findings, the aim of the aNtHESIS project is two-fold. First, to (i) validate the pre-clinical application of our two novel compounds by conducting comprehensive in-vitro and in-vivo tests in mice as well as by carrying out experiments using human CMs. The second aim is (ii) to establish the business feasibility of our cardiac regenerative therapy concept by taking the necessary steps towards the commercialization of our novel compounds, focusing on the creation of strategic alliances with key private sector companies.

Mots-clés : cardiac regeneration,cardiomyocytes,myocardial infarction,dedifferentiation,novel compounds,commercialization
Projet ERC : CodingHeart (Horizon 2020, appel 2017, Advanced grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Max Delbrück Center for Molecular Medicine — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : MDC
Type d'entité : Recherche
Financement ERC de l'entité : 2319514.0 €

Heart failure has become a worldwide epidemic with more than 23 million people affected resulting in devastating consequences for patients and an enormous burden on health care systems. One in five heart failure patients dies within a year of diagnosis and survival estimates after diagnosis are 50% and 10% at 5 and 10 years, respectively. Despite intensive investigation, the molecular mechanisms leading to heart failure remain poorly understood. We will narrow this critical gap in knowledge by proposing a previously unattainable, comprehensive approach to define the genomic architecture and functional consequences of newly identified micropeptides from multiple classes of RNAs that previously were classified to be non-coding in cardiac biology and heart failure. Our approach is unique and novel in several ways. Thematically, our studies focus on novel classes of orphan peptides and their role in heart failure that have not been discovered previously. Our approach relies on innovative interdisciplinary efforts of scientists working in molecular genetics, genomics, computational biology, and cardiovascular research to identify and characterize pathophysiological pathways that converge on these novel peptides. We will identify these short peptides by using genome-wide measures of active translation and will harness unique clinical resources to ensure human relevance. Analysis of animal and cell models coupled with state-of-the-art biochemical and genetic tools will elucidate the function of newly identified micropeptides within the molecular and cellular pathways of cardiac biology and failure. Through these efforts we will discern fundamental causes of maladaptive responses in the heart and strategies to monitor and limit these.

Mots-clés : cardiovascular genetics and genomics,cardiovascular sciences,heart,heart failure,gene expression,long non coding rna,circular rna,functional genomic
Projet ERC : PV-COAT (Horizon 2020, appel 2014, Consolidator grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : Centre Hospitalier Universitaire de Liège — Pays : Belgique — Rôle : Partner
Type d'entité : Recherche
Financement ERC de l'entité : 64680.0 €

Heart valve prostheses are currently among the most widely used cardiovascular devices. To maintain enduring optimal biomechanical properties, the mechanical prostheses, based on carbon, metallic and polymeric components, require permanent anticoagulation, which often leads to adverse reactions, i.e. higher risks of thromboembolism, hemorrhage, and hemolysis. Continuing advances in heart valve prosthesis design and in techniques for implantation have improved the survival length and quality of life of patients who receive these devices. In an ongoing effort to develop a more durable and biocompatible heart valve prosthesis, researchers have used a variety of techniques to determine the suitability of given valve materials for a given implant application. In recent years, advances in polymer science have given rise to new ways of improving artificial cardiovascular devices biostability and hemocompatibility. To date, no polymer coated mechanical prosthetic heart valve exists. The present research project aims to improve the hemocompatibility and long-term in vivo performance of mechanical prosthetic heart valves by reducing contact-induced thrombosis through bioactive polymer prosthetic valve surface coating. These new coated prosthetic heart valves will be designed for hemodynamic performance and durability similar to uncoated materials, combined with a greater thromboresistance, both in vitro and in animal studies. With these promising advances, bioactive surface coated prosthetic heart valves could replace previous generation of prosthetic valves in the near future. The utmost perspective of the current project paves the way for the development of new bioactive coating for other implantable cardiovascular devices or materials.

Mots-clés : mechanical prosthetic heart valves,coating,valve thrombogenicity
Projet ERC : StemBAT (Horizon 2020, appel 2014, Advanced grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Centro de Investigacion Principe Felipe — Pays : Espagne — Rôle : Partner
Acronyme de l'entité : CIPF
Type d'entité : Recherche
Financement ERC de l'entité : 346869.25 €

Here we propose a strategy to control body weight and prevent/reverse obesity based on targeting brown adipose tissue (BAT) to facilitate negative energy balance and prevent adaptive responses to dietary restriction. However, BAT in humans is limited and poorly characterised. Thus, we propose to use stem cells as a tool to gain unique insights into the biology of human brown adipocytes. The General Objective is to identify pathways and factors of potential therapeutic relevance that promote BAT development and/or activation/recruitment using a stem cell based BAT differentiation approach, and then to functionally validate the role of these factors in vitro by genome engineering human stem cell derived adipocytes and in vivo by transplanting these cells into mice. Specific Aims are: 1.To identify molecular mechanisms involved in human brown adipose tissue development and activation. 2. To investigate the molecular mechanisms involved in human white adipose tissue browning/beige cells recruitment 3. To identify new agents/compounds of therapeutic value, able to activate or recruit human brown adipose tissue/brite cells. Experimental strategy: We will use a UCP1-reporter human pluripotent stem cell (PSC) line differentiated into brown and white adipocytes to identify genetic factors that may contribute to brown adipocyte differentiation/activation and white adipocyte browning. Following the identification of candidate genes, we will knock out, constitutively and/or inducibly, both alleles of these genes in human PSC cells, producing a total loss of function. Following the in vitro phenotyping of the cells we will proceed to the in vivo validation of the functional properties/phenotype of human PSC derived brown/brite adipocytes (wild-type and loss of function) by transplanting these cells into mice. Using these reporter tools we will also perform in vitro pharmacological screening and in vivo validation of new compounds that stimulate BAT activation and WAT browning

Mots-clés : brown fat,thermogenesis,obesity
Projet ERC : VALSL (Horizon 2020, appel 2017, Proof of concept grants)
Entité participante : Centre for Genomic Regulation — Pays : Espagne — Rôle : PI
Acronyme de l'entité : CRG;CRG-CERCA
Type d'entité : Recherche
Financement ERC de l'entité : 149894.0 €

Here we propose to test the therapeutic potential of a novel class of reagents, known as splicing-modifying antisense oligonucleotides, in preclinical models of lung adenocarcinoma, including patient-derived tumours in mice. Alternative splicing is a major mechanism of gene regulation by which different messenger RNAs and proteins are generated from a single gene, often displaying distinct, even antagonistic functions. Alterations in alternative splicing have been linked with a plethora of pathologies ranging from neurodegenerative disease to cancer. As a result of detailed mechanistic analyses of alternative splicing regulation in the context of the ERC-funded MASCP project, we have identified antisense oligonucleotides that modulate alternative splicing of a gene that plays key roles in the control of lung cancer cell proliferation. These reagents repress cell growth in vitro as well as inhibit tumour growth when administered intranasally in mouse models of lung adenocarcinoma. The main experimental goal of the ERC PoC proposal is to test the therapeutic value of the antisense oligonucleotides in a variety of patient-derived xenografts in mice, alone or in combination with other treatments, including chemotherapy. This will require previous optimization of dose and delivery route, which is being carried out with available support from other healthcare innovation funds. These goals are aligned with requests from various stakeholders, and funding from the ERC PoC program will be critical for successful valorisation of our assets, intellectual property protection and recruitment of venture capital to establish a spin-off company. Given the high incidence, poor prognosis and lack of efficient therapies for lung cancer, the work proposed can translate fundamental knowledge on molecular mechanisms of gene regulation derived from the ERC-funded MASCP project into applications whose valorisation can bridge the gap to market and provide added value for society.

Mots-clés : lung cancer,adenocarcinoma,splicing modifying therapy,antisense oligonucleotides
Projet ERC : INTEGHER (Horizon 2020, appel 2015, Starting grants)
Domaine scientifique : Life Science
Panel : Immunity, Infection and Immunotherapy
Entité participante : Freie Universität Berlin — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : FU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1810747.0 €

Herpesviruses cause serious diseases in humans and animals. After initial lytic infection, herpesviruses establish a quiescent (latent) infection, which allows their persistence in the host for life. We and others recently identified a novel mechanism that allows maintenance of the genome of certain herpesviruses during latency, by integrating their complete genetic material into host telomeres. One of these viruses is human herpesvirus 6 (HHV-6) which is associated with seizures, encephalitis, and graft rejection in transplant patients. Sporadic reactivation of the integrated virus ensures continued evolution of the virus as it spreads to a new cadre of susceptible individuals. There are critical gaps in our knowledge regarding the fate of herpesvirus genomes during integration and reactivation as well as of viral and cellular factors involved in these processes. INTEGHER will make use of novel technologies to close these gaps and to devise new therapeutic approaches. Specifically, we will 1) determine the fate of the HHV-6 genome during latency by developing a novel reporter system that allows live-cell imaging of the virus genome in living cells and elucidate epigenetic changes of the HHV-6 genome during integration and reactivation; 2) identify viral and cellular factors that drive virus genome integration and reactivation, using recombinant viruses, drugs and CRISPR/Cas9 genome engineering 3) employ genome-editing tools to eliminate the virus genome integrated in host chromosomes in vitro and in an in vivo model. The proposal utilizes state-of-the-art technologies and pioneers new approaches, particularly with regard to visualization and excision of virus genomes in latently infected cells that are also present in (bone marrow) transplants. Altogether, these studies will define the mechanism of herpesvirus integration and reactivation and will provide new tools for therapeutic excision of virus genomes from living cells.