Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
The evolutionary implications of genetic conflict (GENCON)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Evolutionary, population and environmental biology
Countries involved: Sweden
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-05-01
End date: 2017-04-30
Duration (months): 60.0
Total project cost (EUR): 2497442.0
EU funding (EUR): 2497442.0
Participants: 1
Project status: CLOSED

The study of genetic conflict is developing at an almost explosive rate. The recognition that genes or alleles residing in individuals of the two sexes may have conflicting interests is transforming evolutionary biology and, likewise, conflict between genes showing different modes of transmission may fundamentally affect adaptive evolution. The research proposed here will push the frontiers of genetic conflict research and establish new domains. It is aimed at exploring the novel possibility that conflict between mitochondrial and nuclear genes have far-reaching implications for adaptive evolution and at advancing our understanding of the biological consequences of sexual conflict. The project consists of several interrelated parts and will employ insects as model systems. First, I will assess to what extent genetic variation in fitness is sexually antagonistic and what life history traits contribute to sexually antagonistic variation. Second, I will elucidate the genomics of metabolic rate and measure selection on metabolic phenotypes. Third, I will test whether sexually antagonistic epistatic interactions between mitochondrial and nuclear genes generate conflict over metabolic rate. Fourth, I will test the hypothesis that sexual conflict contribute to the evolution of primary and secondary sexual traits. Fifth, I will shed light on the complicated evolutionary interplay between sexual conflict and mating system evolution. I will employ an innovative research strategy, ‘experimental genomics’, in which genomic data is used to guide experimental evolutionary work with distinct genotypes. The research outlined here will collectively provide an unprecedented wealth of information into the role of genetic conflict in several horizons of adaptive evolution, ranging from DNA sequence evolution over life history evolution to speciation, and will set the standard for a new generation of insightful studies aimed at bridging the gap between phenotypic selection and genomics.

Keywords: genetic conflict,mtdna evolution,thermal adaptation,frequency dependent selection,sexual selection,metabolism,life history evolution,global warming,speciation
Reinforcing cooperation between the Royal Botanic Garden of Jordan and ERA (BOT-ERA)

Framework: FP7 — Capacities
Programme: Activities of International Cooperation
Destination: Reinforcing cooperation with Europe's neighbours in the context of the ERA
Action type: Coordination and support actions
Countries involved: United Kingdom,United Kingdom,Jordan,Luxembourg
Call:  (FP7-INCO-2011-6, 2011)
Start date: 2012-02-01
End date: 2015-01-31
Duration (months): 36.0
Total project cost (EUR): 554802.81
EU funding (EUR): 497570.0
Participants: 4
Project status: CLOSED

Jordan is rich in flora with over 2500 species including 363 species of vascular plants. It is situated at the Southern edge of the Fertile Crescent and is a hotspot for crop, crop wild relative and medicinal plant diversity of vital global importance. However, due to pressures associated with desertification, many of Jordan's plant habitats are threatened or on the verge of extinction. About 35% of all Jordanian flora can be found at the Royal Botanic Garden of Jordan (RBG). RBG is the only botanical garden in Jordan. It was established by the Ministry of Environment to implement the 1992 Convention on Biological Diversity and its mission is to conserve regional biodiversity on the habitat level. RBG is well networked with agricultural, environmental and tourism organisations throughout Jordan and the surrounding region and acts as a natural focal point for botanical and conservation research. Via BOT-ERA, RBG aims to become more closely integrated with ERA through capacity building and strategic collaboration with three excellent European research and innovation organisations: Royal Botanic Gardens - Kew, University of Birmingham, and Innoveo Consulting. The focus of the capacity building will be on three key botanical research topics: A) Plants and Seed Conservation, B) Genetic Resource Diversity and Biotechnology, and C) Utilisation and Access Benefit Sharing. These are research topics highly relevant to the FP7 KBBE and Environment. The BOT-ERA project will last 36 months and be implemented by a dedicated team of experienced RBG researchers. It will be overseen by a steering committee involving the consortium partners plus members of the Ministry of Agriculture, Ministry of Environment, NCARE, ICARDA and Royal Marine Conservation Society of Jordan. The regional environmental, social and economic impacts expected from the BOT-ERA project are precisely the reasons why these organisations have signed letters of support for the proposal.

Keywords: royal botanic garden,plants and seed conservation,genetic diversity and biotechnology,utilisation and access benefit sharing
Using novel methodologies to target and image cancer invasion and therapeutic resistance (CANCERINNOVATION)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Diagnostic tools, therapies and public health
Countries involved: United Kingdom
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-08-01
End date: 2017-07-31
Duration (months): 60.0
Total project cost (EUR): 2499000.0
EU funding (EUR): 2499000.0
Participants: 1
Project status: CLOSED

We aim to develop and apply a suite of new technologies in a novel cancer discovery platform that will link high-definition cancer biology, via state-of-the-art disease imaging and pathway modelling, with development of novel interrogative and therapeutic interventions to test in models of cancer that closely resemble human disease. The work will lead to a new understanding of cancer invasion, how to treat advanced disease in the metastatic niche, how to monitor therapeutic responses and the compensatory mechanisms that cause acquired resistance. Platform development will be based on combined, cross-informing technologies that will enable us to predict optimal ‘maintenance therapies’ for metastatic disease by targeting cancer evolution and spread through combination therapy. A key strand of the platform is the development of quantitative multi-modal imaging in vivo by use of optical window technology to inform detailed understanding of disease and drug mechanisms and predictive capability of pathway biomarkers. Innovative methodologies are urgently needed to address declining approval rates of novel medicines and the unmet clinical needs of treating cancer patients in the advanced disease setting, where tumour spread and survival generally continues unchecked by current therapies. This work will be largely pre-clinical, but will always be mindful of the clinical problem in managing late stage human disease through rationale design of combination therapies with companion diagnostic tests. The cancer survival statistics will be changed if we can curb continuing spread of aggressive, metastatic disease and resistance to therapy by taking smarter combined approaches that make best use of emerging technologies in an innovative way, particularly where they are more predictive of clinical efficacy.

Keywords: cancer discovery science: new methodology and imaging platform - pre-clinical drug studies
Generating self-antigen diversity in the thymus: from gene expression patterns in single cells to the system level, an integrative approach (SELF-TOLERANCE)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Immunity and infection
Countries involved: Germany
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-06-01
End date: 2017-11-30
Duration (months): 66.0
Total project cost (EUR): 2014560.0
EU funding (EUR): 2014560.0
Participants: 1
Project status: CLOSED

The thymus plays a central role in the induction of self-tolerance, a hallmark of the immune system. During T cell development a highly diverse T cell receptor repertoire is probed against a matching array of self-antigens. While the generation of the T cell receptor repertoire relies on unique genetic recombination mechanisms, the corresponding molecular principles underlying the generation of TCR ligands - self-peptide/MHC complexes - are less well understood; recent data indicate that novel principles of epigenetic control are employed. This proposal aims at understanding a unique feature of thymic epithelial cells (TECs), namely the expression of a multitude of tissue-restricted antigens (TRAs), a phenomenon termed promiscuous gene expression (pGE) in the context of self-tolerance. The integrative approach of this proposal has 4 main objectives (i) a characterization of the molecular control of different pools of pGE beyond the role of the Autoimmune Regulator (Aire) in relation to the developmental biology of TECs (ii) a comprehensive and comparative analysis of expression patterns of TRAs in single cells of different species in relation to epigenetic signatures and higher chromatin order, (iii) translating these findings to the cellular dynamics and topology of the thymic medullary compartment, e.g. individual mTEC clones in situ (iv) the modelling of these different levels of analysis by a system biology approach, e.g. testing our hypothesis that clusters of TRAs in the genome represent an “operational unit” of pGE. We expect from these studies new basic insights into a fascinating and still arcane aspect of the vertebrate immune system, which will also contribute to our understanding of the etiology and pathophysiology of human autoimmune diseases.

Keywords: central tolerance,promiscuous gene expression,gene coregulation,thymic microenvironment
The architecture of adaptation to novel environments (ARCHADAPT)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Evolutionary, population and environmental biology
Countries involved: Austria
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-07-01
End date: 2018-06-30
Duration (months): 72.0
Total project cost (EUR): 2452084.0
EU funding (EUR): 2452084.0
Participants: 1
Project status: CLOSED

One of the central goals in evolutionary biology is to understand adaptation. Experimental evolution represents a highly promising approach to study adaptation. In this proposal, a freshly collected D. simulans population will be allowed to adapt to laboratory conditions under two different temperature regimes: hot (27°C) and cold (18°C). The trajectories of adaptation to these novel environments will be monitored on three levels: 1) genomic, 2) transcriptomic, 3) phenotypic. Allele frequency changes during the experiment will be measured by next generation sequencing of DNA pools (Pool-Seq) to identify targets of selection. RNA-Seq will be used to trace adaptation on the transcriptomic level during three developmental stages. Eight different phenotypes will be scored to measure the phenotypic consequences of adaptation. Combining the adaptive trajectories on these three levels will provide a picture of adaptation for a multicellular, outcrossing organism that is far more detailed than any previous results. Furthermore, the proposal addresses the question of how adaptation on these three levels is reversible if the environment reverts to ancestral conditions. The third aspect of adaptation covered in the proposal is the question of repeatability of adaptation. Again, this question will be addressed on the three levels: genomic, transcriptomic and phenotypic. Using replicates with different degrees of genetic similarity, as well as closely related species, we will test how similar the adaptive response is. This large-scale study will provide new insights into the importance of standing variation for the adaptation to novel environments. Hence, apart from providing significant evolutionary insights on the trajectories of adaptation, the results we will obtain will have important implications for conservation genetics and commercial breeding.

Keywords: population genetics,experimental evolution,adaptation,next generation sequencing
Perineuronal net treatments for neurodegenerative disease (ECMNEURO)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Neurosciences and neural disorders
Countries involved: United Kingdom
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-03-01
End date: 2017-02-28
Duration (months): 60.0
Total project cost (EUR): 2450543.0
EU funding (EUR): 2450543.0
Participants: 1
Project status: CLOSED

Inhibitory chondroitin sulphate proteoglycans (CSPGs) have several roles in CNS damage and repair, revealed by their digestion with chondroitinase. Most recently, digestion of CSPGs in the limbic system and cortex has led to a very substantial enhancement of memory. The effects of CSPGs on plasticity and memory are largely through their concentration into PNNs, because transgenics lacking the PNN component link protein in the CNS have very attenuated PNNs, and show continuing plasticity into adulthood, and enhanced memory in just the same way as chondroitinase-treated animals. The PNN is therefore a novel therapeutic target that has not been explored. This application focuses particularly on enhancement of memory through manipulation of PNNs. In Alzheimer’s disease (AD) and ageing the main cognitive disability is loss of memory. The enhancement of memory following chondroitinase treatment or PNN knockout in object memory is many times greater than obtained using cholinesterase inhibitors (the only currently available treatment for memory enhancement). PNN manipulation is therefore a particularly promising avenue for developing treatments to overcome the main cognitive disability of AD and ageing. The aims of the application are: 1. Test the extent of memory enhancement due to PNN manipulation in models of AD due to Abeta, tau mutations and in aged CNS. 2. Establish the molecular mechanism for PNN effects on memory, focusing on Semaphorin3 presentation by PNNs, and direct effects via the PTPsigma receptor. 3. Discover the sulphation modifications of the CSPG glycan chains that enable binding of Semaphorin3s, activation of the PTPsigma receptor. 4. Analyse molecules that bind to PNN glycans, to identify new potential effectors of PNN effects on memory and plasticity 5. Testing in memory and plasticity models of novel PNN-targeted approaches.

Keywords: chondroitin sulphate proteoglycans memory alzheimers disease ageing semaphorins
Immunogenetics of Severe Bacterial Disease Susceptibility and Vaccine Responses in Humans (IMMUNOGENE)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Immunity and infection
Countries involved: United Kingdom
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-06-01
End date: 2017-05-31
Duration (months): 60.0
Total project cost (EUR): 1997927.0
EU funding (EUR): 1997927.0
Participants: 4
Project status: CLOSED

Defining the genetic basis of differential susceptibility to infectious diseases is of importance for understanding the evolution of human genetic diversity, for identifying critical molecular pathways in disease resistance, and for the design of novel intervention strategies such as more effective vaccines. I propose to sequence the entire coding regions of all human genes in large numbers of cases of severe tuberculosis and fatal bacterial sepsis to identify variants that have a large impact on risk of developing severe tuberculosis or dying from sepsis. I shall then apply this exome sequencing approach to define the genetic basis of variable immune responsiveness in West Africans to hepatitis B vaccine, and to a new promising T cell-inducing vaccine, developed in my group, that targets the liver-stage of malaria. This programme will benefit from unique collections of 10,000 disease cases and in-house expertise in vaccine design, bioinformatics and statistical genetics, and will take genetic investigation of common infectious disease to near the ultimate level of analysis by using large-scale next generation sequencing.

Keywords: tuberculosis,sepsis,malaria,vaccine,exomics,suceptibility,genomics,polymorphism
Epigenetics and microRNAs in Myocardial Function and Disease (CARDIOEPIGEN)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: ERC Advanced Grant Interdisciplinary Panel
Countries involved: Italy
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-10-01
End date: 2018-09-30
Duration (months): 72.0
Total project cost (EUR): 2500000.0
EU funding (EUR): 2500000.0
Participants: 1
Project status: CLOSED

Heart failure (HF) is the ultimate outcome of many cardiovascular diseases. Re-expression of fetal genes in the adult heart contributes to development of HF. Two mechanisms involved in the control of gene expression are epigenetics and microRNAs (miRs). We propose a project on epigenetic and miR-mediated mechanisms leading to HF. Epigenetics refers to heritable modification of DNA and histones that does not modify the genetic code. Depending on the type of modification and on the site affected, these chemical changes up- or down-regulate transcription of specific genes. Despite it being a major player in gene regulation, epigenetics has been only partly investigated in HF. miRs are regulatory RNAs that target mRNAs for inhibition. Dysregulation of the cardiac miR signature occurs in HF. miR expression may itself be under epigenetic control, constituting a miR-epigenetic regulatory network. To our knowledge, this possibility has not been studied yet. Our specific hypothesis is that the profile of DNA/histone methylation and the cross-talk between epigenetic enzymes and miRs have fundamental roles in defining the characteristics of cells during cardiac development and that the dysregulation of these processes determines the deleterious nature of the stressed heart’s gene programme. We will test this first through a genome-wide study of DNA/histone methylation to generate maps of the main methylation modifications occurring in the genome of cardiac cells treated with a pro-hypertrophy regulator and of a HF model. We will then investigate the role of epigenetic enzymes deemed important in HF, through the generation and study of knockout mice models. Finally, we will test the possible therapeutic potential of modulating epigenetic genes. We hope to further understand the pathological mechanisms leading to HF and to generate data instrumental to the development of diagnostic and therapeutic strategies for this disease.

Keywords: heart failure
Oncogene-Induced DNA Damage in Cancer (ONIDDAC)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Physiology, Pathophysiology and Endocrinology
Countries involved: Switzerland
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-05-01
End date: 2018-04-30
Duration (months): 72.0
Total project cost (EUR): 2499351.0
EU funding (EUR): 2499351.0
Participants: 1
Project status: CLOSED

I recently proposed a model that helps explain the presence of p53 mutations and genomic instability in human cancers (Nature, 2005; Nature 2006; Science 2008). The key features of this model are that oncogenes induce DNA replication stress, which in turn leads to DNA double-strand breaks, genomic instability and p53-induced senescence or apoptosis. This model is relevant for almost all cancer types and explains the spectrum of mutations being reported in thousands of human cancers by the cancer sequencing consortia. In this project, I propose to take the next logical steps that follow from my discovery. Specifically, I propose the following objectives: 1. Elucidate the mechanisms by which oncogenes induce DNA replication stress. Oncogene-induced genomic deletions map within very large actively transcribed genes. Accordingly, I hypothesize that oncogenes and transcription synergistically disrupt pre-replicative complexes resulting in large genomic regions that have a low density of replication initiation events. To test this hypothesis, I propose to introduce by site-directed homologous recombination a transcription termination sequence at the beginning of very large gene and determine whether it remains sensitive to oncogene-induced genomic instability. Genome-wide transcription and DNA replication patterns will also be examined in cells that are sensitive to oncogene-induced DNA replication stress (most somatic cells and cell lines) and cells that are resistant (induced pluripotent stem cells). 2. Identify and characterize genes necessary for proliferation of cells with oncogene-induced DNA replication stress. Using high throughput siRNA screens we will identify genes, whose depletion inhibits proliferation of cells with oncogene-induced DNA replication stress, without affecting normal cells. We will explore the function of these genes using molecular biology, structural biology and genetic approaches. Some promising candidates have already been identified.

Keywords: cancer,replication stress,genome stability,replication fork,oncogene,p53,53bp1,dna damage response,cell cycle checkpoint,break-induced replication