Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : TiDrugArchitectures (Horizon 2020, appel 2015, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Synthetic Chemistry and Materials
Entité participante : Hebrew University of Jerusalem — Pays : Israël — Rôle : PI
Acronyme de l'entité : HUJI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2000000.0 €

This proposal aims to develop custom designed anticancer therapeutic frameworks that are effective, stable, safe, and tumor targeted, based on the biocompatible TiIV metal. The Tshuva group has established that water stable phenolato TiIV complexes are especially effective as anticancer agents both in vitro and in vivo, with markedly reduced side effects. Optimal derivatives will be developed to combine activity, stability, and biological accessibility, by maintaining small steric bulk while incorporating strong binding donors and hydrophilicity. The mechanism of action will be investigated by chemical and biological methods, including analyzing bio-distribution, cellular pathways and targets, and interaction with bio-molecules. Specifically, the active metal centers will be linked to bioactive moieties through redox-sensitive S–S bonds to enable tumor targeting. Cell penetrating peptides will facilitate cellular penetration for redox-dependent release of the active species selectively in cancer cells; steroid moieties will direct selectivity to hormone-dependent cancer cell types. Since the combination of TiIV- with Pt-based drugs has shown synergistic effects, multi-active entities will include two or more metal centers, possibly also linked to a transport unit. In addition to linear conjugates, polymeric and dendritic assemblies, exploiting the enhanced permeability of cancer cells, will be constructed with theoretically unlimited options for targeted delivery of multiple active sites. Most importantly, flexible well-defined redox-sensitive cages, as well as rigid pH sensitive complex cages, constructed with customized 3D geometries, will enable specific targeting of any active compound or conjugate and selective dissociation only where desired. This study should yield superior anticancer drugs, while unraveling the mystery of their complex biochemistry, and will contribute to the development of novel chemical and medicinal research directions and applications.
Projet ERC : CD4DNASP (Horizon 2020, appel 2015, Starting grants)
Domaine scientifique : Life Science
Panel : Immunity, Infection and Immunotherapy
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 : 1500000.0 €

This proposal aims to investigate the role of cytosolic DNA sensing pathways in CD4 T cell differentiation. Cellular host defense to pathogens relies on the detection of pathogen-associated molecular patterns including deoxyribonucleic acid (DNA), which can be recognized by host myeloid cells through Toll-like receptor (TLR) 9 binding. Recent evidence however suggests that innate immune cells can also perceive cytoplasmic DNA from infectious or autologous origin through cytosolic DNA sensors triggering TLR9-independent signaling. Activation of cytosolic DNA sensor-dependent signaling pathways has been clearly shown to trigger innate immune responses to microbial and host DNA, but the contribution of cytosolic DNA sensors to the differentiation of CD4 T cells, an essential event for shaping adaptive immune responses, has not been documented. This proposal aims to fill this current knowledge gap. We aim to decipher the molecular series of transcriptional events triggered by DNA in CD4 T cells that ultimately result in altered T cell differentiation. This aim will be addressed by combining in vitro and in vivo approaches such as advanced gene expression analysis of CD4 T cells and use of transgenic and gene-deficient mice. Structure activity relationship and biophysical studies will also be performed to unravel novel immunomodulators able to affect CD4 T cell differentiation.

Mots-clés : cd4 t cell differentiation,gene transcription regulation,thermodynamics of protein,dna complexes
Projet ERC : ORDINARY (Horizon 2020, appel 2017, Consolidator grants)
Domaine scientifique : Social Sciences and Humanities
Panel : Individuals, Markets and Organisations
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 : 1555679.0 €

This proposal aims to measure, document, and understand the historical origins of contemporary African inequality that has a strong ethnic component. The focus is on the interplay of the nation and the ethnicity that co-evolve, sometimes violently and sometimes peacefully across the continent. The proposal consists of four closely related projects. The first project develops a large database portraying the evolution of inequality and intergenerational mobility in education covering the full post-independence period using census data from many countries. Decomposing inequality and mobility in education into a between-ethnicity and a within-ethnicity component, it provides an autopsy of the cross-country, cross-region, and dynamic patterns. Then it examines the mechanisms linking inequality with well-being, employing a plethora of geo-referenced micro data. The second project extends widely-used anthropological maps and cross-cultural data on pre-colonial Africa to examine the legacy of deeply-rooted ethnic-specific institutional and economic traits on development. The project aims exploring the key mechanisms and examining exactly which aspects of statehood (courts, land rights, bureaucracy) matter for development. The third project assesses the impact of colonial “divide-and-rule” strategies and ethnic-based favouritism/discrimination on contemporary African political economy. To this end it compiles an original database of ethnic power relations during colonization and then examines whether ethnic political power and inequality post-independence is related to the differential treatment of ethnicities from the colonial administration. The fourth project assesses the long-run development impact of colonial concessions to private corporations and their main features (e.g., forced labour, violence, method of extraction), compiling a pan-African dataset covering all concessions and applying state-of-the-art econometric techniques to establish causal relationships.

Mots-clés : africa,instititions,ethnicity,history,political economy,colonisation,inequality,mobility
Projet ERC : DRANOEL (Horizon 2020, appel 2016, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Universe sciences
Entité participante : Universität Hamburg — Pays : Allemagne — Rôle : Partner
Acronyme de l'entité : UHH
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 278250.0 €

This proposal aims to understand the origin of the radio emission detected in the most massive objects in our Universe: galaxy clusters. The extreme physical conditions in the intra-cluster medium of galaxy clusters are beyond anything achievable in any laboratory on Earth. The space in between the galaxies is filled with an extremely hot and diluted gas that hosts the largest-scale magnetic fields known so far. A big challenge of modern astrophysics is understanding the origin of radio emission spread over huge swathes in some clusters. This emission is a mystery because it requires relativistic electrons moving around magnetic field lines, but both the origin of the magnetic fields and of the electrons are unknown. Absolutely fundamental to the understanding of the radio emission are a detailed knowledge of the magnetic fields and of the energy spectrum of the emitting particles. We are stepping into a new era of observational astronomy, in which surveys will be conducted rather than single pointed observations. This survey era is changing our approach to observational data. It enables to perform all-sky studies but calls for numerical and technological efforts for the data handling. Taking advantage of the advent of new radio and X-ray facilities, such as LOFAR, the JVLA, ASKAP, and eROSITA, this project wants to understand the origin of the radio emission, its evolution and its connections with the cluster dynamics. We have today the unprecedented opportunity to discover the physical processes at work in these unique environments, that link the micro-physical processes at work in galaxy clusters with the clusters' macro-physics. The proposed study will address fundamental questions not restricted to the physics of galaxy clusters but having impact on several inter-connected physical disciplines, such as cosmology, astro-particle physics and plasma physics.

Mots-clés : non thermal emission,magnetic fields,radio observations
Projet ERC : mtDNA-CURE (Horizon 2020, appel 2016, Advanced grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
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 : 2500000.0 €

This proposal describes a series of powerful experimental strategies to develop a completely novel treatment for mtDNA mutation disease based on identifying unknown mechanisms controlling mtDNA replication. Several hundred different mtDNA mutations affect tRNA genes and impair mitochondrial translation leading to human disease. There is typically heteroplasmy with a mixture of wild-type and mutated mtDNA, and the mutations are acting in a “recessive” (loss of function) way. Very high levels of mutated mtDNA are needed to cause disease in affected patients whereas maternal relatives with high, but sub-threshold levels of mutated mtDNA are completely healthy. The corollary of these observations is that even a small increase of wild-type mtDNA may efficiently counteract disease in affected patients. This hypothesis will be validated by a series of genetic experiments with mice harbouring single pathogenic mtDNA mutations. Furthermore, novel factors controlling mtDNA replication will be identified. In particular, we will elucidate the formation and function of the mammalian displacement (D) loop, which provides a switch between abortive and genome length mtDNA replication. This very fundamental problem in mammalian mitochondrial biology has remained unsolved for decades, but I feel that the innovative experimental strategies I present in this proposal are very powerful and should have a fair chance of being successful. In any circumstance, the project will provide important molecular insights into novel mechanisms relevant for mammalian mtDNA replication. Over the years I have been strongly convinced that congruent results from in vivo and in vitro studies are needed to obtain reliable mechanistic insights and this project is therefore based on the close integration of biochemistry, advanced proteomics and state-of-the-art mouse and fly genetics. Finally, I describe a powerful large-scale screening approach to develop small molecular stimulators of mtDNA replication.

Mots-clés : mitochondria,mtdna mutation disease,mtdna replication
Projet ERC : VACCIBIOME (Horizon 2020, appel 2018, Advanced grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : University of Trento — Pays : Italie — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 962500.0 €

This proposal intends to shed light on the interplay between cancer immunity and gut microbiome as a way to optimize personalized cancer vaccines and immunotherapy. The project originates from two milestone discoveries. First, to be effective cancer immunotherapies have to target CD4+/CD8+ T cell neo-epitopes, which originate from tumor mutations. Second, the gut microbiome influences the effectiveness of anti-PD-1/PD-L1 antibody immunotherapy both in animal models and in humans. We also recently showed in a mouse model that oral gavages with Bifidobacterial cocktails improved the therapeutic power of neo-epitope-based cancer vaccines. How microbiome affects anti-cancer immunity has not been fully elucidated yet and a deep understanding of the underlying mechanisms has the potential to substantially improve cancer immunotherapy. Since microbiome antigens are processed and presented by antigen-presenting cells and microbiome-induced T cells represent large fraction of the peripheral T cell repertoire, our hypothesis is that this large repertoire includes T cells which cross-react with cancer neo-epitopes (“molecular mimicry (MM)”). Depending upon the composition of gut microbiome, cross-reacting T cells can positively or negatively modulate anti-tumor immunity. To demonstrate the role of MM in cancer immunity this project intends (i) to select the cross-reactive T cell epitopes as predicted by meta-omics analysis of gut microbiome and exome/transcriptome analysis of cancer cell lines, (ii) to formulate vaccines containing different combination of cross-reactive epitopes, and (iii) to test vaccine anti-tumor activities in normal mice, gnotobiotic mice and mice with engineered microbiome. The ultimate goals are: 1) to provide new criteria for neo-epitope selection in personalized cancer vaccines, 2) to develop prognostic tools based on microbiome analysis, and 3) to define microbial species to be used as immune-potentiators in patients undergoing cancer therapy.

Mots-clés : cancer vaccines,microbiota,neo epitopes,molecular mimicry
Projet ERC : VACCIBIOME (Horizon 2020, appel 2018, Advanced grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : Toscana Life Sciences — Pays : Italie — Rôle : Partner
Acronyme de l'entité : TLS
Type d'entité : Recherche
Financement ERC de l'entité : 1487500.0 €

This proposal intends to shed light on the interplay between cancer immunity and gut microbiome as a way to optimize personalized cancer vaccines and immunotherapy. The project originates from two milestone discoveries. First, to be effective cancer immunotherapies have to target CD4+/CD8+ T cell neo-epitopes, which originate from tumor mutations. Second, the gut microbiome influences the effectiveness of anti-PD-1/PD-L1 antibody immunotherapy both in animal models and in humans. We also recently showed in a mouse model that oral gavages with Bifidobacterial cocktails improved the therapeutic power of neo-epitope-based cancer vaccines. How microbiome affects anti-cancer immunity has not been fully elucidated yet and a deep understanding of the underlying mechanisms has the potential to substantially improve cancer immunotherapy. Since microbiome antigens are processed and presented by antigen-presenting cells and microbiome-induced T cells represent large fraction of the peripheral T cell repertoire, our hypothesis is that this large repertoire includes T cells which cross-react with cancer neo-epitopes (“molecular mimicry (MM)”). Depending upon the composition of gut microbiome, cross-reacting T cells can positively or negatively modulate anti-tumor immunity. To demonstrate the role of MM in cancer immunity this project intends (i) to select the cross-reactive T cell epitopes as predicted by meta-omics analysis of gut microbiome and exome/transcriptome analysis of cancer cell lines, (ii) to formulate vaccines containing different combination of cross-reactive epitopes, and (iii) to test vaccine anti-tumor activities in normal mice, gnotobiotic mice and mice with engineered microbiome. The ultimate goals are: 1) to provide new criteria for neo-epitope selection in personalized cancer vaccines, 2) to develop prognostic tools based on microbiome analysis, and 3) to define microbial species to be used as immune-potentiators in patients undergoing cancer therapy.

Mots-clés : cancer vaccines,microbiota,neo epitopes,molecular mimicry
Projet ERC : PADRE (Horizon 2020, appel 2020, Consolidator grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : University of Helsinki — Pays : Finlande — Rôle : PI
Acronyme de l'entité : UH
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1155415.0 €

This proposal introduces a next-generation platform for next generation optimally personalised drug therapy: on-demand drug releasing implants triggered and controlled by blue/UV light. The technology is based on novel light generation pathways and a light-sensitive nanocellulose drug reservoir. A formidable physiological barrier for light-triggered drug release has been the inability to use high-energy blue/UV light as the triggering signal. This is because the penetration depth of light drops to from a few cm to under 100 micrometers when moving from near-infrared to UV light, making deeper targets within tissues accessible only to red light. However, red light, with its intrinsically lower energy, has limited value in photochemical reactions because the photocleavage of covalent bonds typically requires UV-light. This is why many groups are looking at e.g. red-to-blue photon upconversion strategies. The major objective in PADRE is to circumvent the issue of unavailable blue light in implants through local light generation. Having access to light with higher energy will enable a much wider chemical toolbox, including photocleavable linkers. I will use blue/UV light to trigger and precisely control drug release. The approach creates an unconventional way to modulate the release profiles without unwanted drug leakage. The light will be generated through either 1) photon upconversion, or 2) integrated light sources. With the first approach, I will pioneer efficient red-to-blue/UV triplet-triplet annihilation upconversion in a hydrogel environment, while in the second approach I will generate light by a co-implanted light source. Both approaches are feasible according to my preliminary results on efficient triplet-triplet annihilation upconversion and photoresponsive liposomes and will be demonstrated in a working implant prototype. The core breakthrough of PADRE will be a viable solution to employ blue excitation in precisely-tailored drug-releasing implants.

Mots-clés : liposomes,controlled drug release,nanocellulose,photon upconversion,medical devices,implant
Projet ERC : THERACAN (Horizon 2020, appel 2015, Advanced grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Spanish National Cancer Research Centre — Pays : Espagne — Rôle : PI
Acronyme de l'entité : CNIO
Type d'entité : Recherche
Financement ERC de l'entité : 2499500.0 €

This proposal is aimed at identifying and functionally validating targets with potential therapeutic value to devise novel strategies to treat two human cancers with unacceptable low survival rates and unmet medical needs: pancreatic ductal adenocarcinoma and K-RAS mutant lung adenocarcinoma. Although these tumor types have distinct pathological and clinical manifestations, they are both driven by K-RAS mutations. Hence, we expect that the proposed studies will generate synergies to accelerate the outcome of the expected results. In the first part of the proposal, we will identify those genes activated in the cancer initiating cells responsible for the onset of pancreatic and lung tumors. We reasoned that genes implicated in the initial stages of tumor development will be maintained during tumor evolution and not be affected by the intra-tumoral heterogeneity generated during tumor progression. We also propose to identify and validate genes capable of reprogramming the desmoplasic stroma characteristic of pancreatic tumors to hamper its pro-tumoral effects. Likewise, we intend to define the molecular events that control senescence, a naturally occurring process that serves as a barrier to tumor development. In the second part of the project, we will interrogate the role of known targets with suspected therapeutic value in tumor progression using a new generation of GEM tumor models that allow the temporal separation of tumor development from target ablation or inactivation. These studies will make it possible to design combination therapies capable of effectively eradicate advanced tumors. The last section of this proposal focuses on the pharmacological validation of these combination therapies using best-in-class inhibitors in state-of-the-art preclinical trial platforms based on GEM and PDX tumor models. The results derived from these studies will guide the design of new clinical trials that should have a positive impact in the treatment of these deadly diseases.

Mots-clés : pancreatic cancer,lung cancer,mouse models
Projet ERC : HD-DittoGraph (Horizon 2020, appel 2016, Advanced grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : University of Milan — Pays : Italie — Rôle : PI
Acronyme de l'entité : UNIMI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1868443.0 €

This proposal is aimed at identifying the molecular mechanisms that have brought the human Huntington Disease-causing Huntingtin (Htt) exon 1, with its pure and unstable CAG repeat, to be shaped the way it is today. Specifically, we intend to screen for genetic elements affecting Htt repeat length instability in dividing and postmitotic neuronal cells. The novelty of our approach relies on the construction of a human embryonic stem (hES) cell platform that couples highly efficient CRISPR/Cas9 technology with genome-wide screenings and third generation sequencing, to test the contribution of thousands of unequivocally barcoded cis and trans modifiers on Htt exon 1 repeats instability. In Aim 1, we will test the contribution of cis-modifiers to repeat instability during multiple mitotic divisions, by generating a hES cell platform where we will subsequently introduce a barcoded donor library of different Htt exon 1 constructs, with different CAG and flanking sequences, at the Htt locus. In Aim 2 our hES cell platform will be implemented with inducible Cas9 elements and sgRNAs libraries to perform genome-wide loss and gain of function (LOF, GOF) screenings of trans-acting modifiers of repeat sequence and size. The sgRNAs will act as barcodes for the modifier genes, allowing to test their causative role on repeat size changes. In Aim 3, we will exploit the neurogenic potential of hES cells in our LOF and GOF platforms to identify Htt exon 1 repeat modifiers in differentiating striatal neurons. Candidate modifier genes will be individually validated and tested for their functional impact on gene networks by transcriptome analysis. In all approaches, third generation sequencing and ad hoc computational pipelines will allow the simultaneous identification of the repeat changes and their association to the corresponding modifiers. Overall, this research proposal is expected to provide key molecular and genetic insights into the process of Htt repeat expansion in human

Mots-clés : huntington s disease,cag repeats,stem cells,genome editing,crispr,cas9 technology,cell platform,third generation sequencing,high throughput screening