Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Synthetic metabolic pathways for carbon fixation (SYMPAC)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Genetics,Genomics,Bioinformatics and Systems Biology
Countries involved: Israel
Call:  (ERC-2010-StG_20091118, 2010)
Start date: 2011-01-01
End date: 2015-12-31
Duration (months): 60.0
Total project cost (EUR): 1498792.0
EU funding (EUR): 1498792.0
Participants: 1
Project status: CLOSED

Carbon fixation is the main pathway for storing energy and accumulating biomass in the living world. It is also the principal reason for humanity s utilization of land and water. Under human cultivation, carbon fixation significantly limits growth. Hence increasing carbon fixation rate is of major importance towards agricultural and energetic sustainability. Are there limits on the rate of such central metabolic pathways? Attempts to improve the rate of Rubisco, the key enzyme in the Calvin-Benson cycle, have achieved very limited success. In this proposal we try to overcome this bottleneck by systematically exploring the space of carbon fixation pathways that can be assembled from all ~4000 metabolic enzymes known in nature. We computationally compare all possible pathways based on kinetics, energetics and topology. Our initial analysis suggests a new family of synthetic carbon fixation pathways utilizing the most effective carboxylating enzyme, PEPC. We propose to experimentally test these cycles in the most genetically tractable context by constructing an E. coli strain that will depend on carbon fixation as its sole carbon input. Energy will be supplied by compounds that cannot be used as carbon source. Initially, we will devise an autotrophic E. coli strain to use the Calvin-Benson Cycle; in the next stage, we will implement the most promising synthetic cycles. Systematic in vivo comparison will guide the future implementation in natural photosynthetic organisms. At the basic science level, this proposal revisits and challenges our understanding of central carbon metabolism and growth. Concomitantly, it is an evolutionary experiment on integration of a biological novelty. It will serve as a model for significantly adapting a central metabolic pathway.

Keywords: carbon fixation,synthetic biology,sustainability
Microbial adaptation within ecosystems (ECOADAPT)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Evolutionary, population and environmental biology
Countries involved: Portugal
Call:  (ERC-2010-StG_20091118, 2010)
Start date: 2010-12-01
End date: 2015-11-30
Duration (months): 60.0
Total project cost (EUR): 1167600.0
EU funding (EUR): 1167600.0
Participants: 1
Project status: CLOSED

All natural populations are constantly subject to new mutations, and frequently face new environments, to which they adapt. Knowledge of the genetics of adaptation should provide the centerpiece of a unified theory of evolution. Despite its extreme importance, the process of adaptation is far from being understood. How does the shape of distribution of fitness effects of mutations depend on the environment? What is the importance of epistasis in adaptive evolution? are still open questions. While empirical observations on advantageous mutations are extremely difficult, recent technical advances allow us to start tackling these questions with an unprecedented accuracy. Here we will combine different methods in a novel powerful marker system to track adaptive mutations as they become incorporated into bacterial populations adapting to different environments and as they fix. Interestingly theory suggest that some generalities may underlie the process of adaptation and that ecology may be important in the dynamics and statistical laws of adaptation. Experimental evolution with bacteria presents us with the opportunity to directly measure key parameters and to test theoretical predictions about the genetic basis of adaptive evolution in increasingly complex ecosystems. As Dobzansky pointed out The greater the diversity of inhabitants in a territory, the more adaptive opportunities exist in it. The main goal of this research project is to measure rates and effects of adaptive mutations, as well as patterns of epistasis amongst beneficial mutations in environments with different strengths of abiotic versus biotic interactions.

Keywords: microbial adaptation,fitness landscapes,computer simulation,mutation,epistasis,predation
The molecular basis of Cockayne Syndrome (MOBA-CS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Molecular and Structural Biology and Biochemistry
Countries involved: Switzerland
Call:  (ERC-2010-StG_20091118, 2010)
Start date: 2011-01-01
End date: 2015-12-31
Duration (months): 60.0
Total project cost (EUR): 1499235.0
EU funding (EUR): 1499235.0
Participants: 2
Project status: CLOSED

Cockayne syndrome is a congenital disease with impaired DNA repair in actively transcribed genes. Affected children show developmental abnormalities and signs of premature aging. Cockayne syndrome is caused by mutations in the Cockayne syndrome complementation group A (CSA) and B (CSB) genes. While CSB encodes a SWI/SNF ATPase that likely assists the stalled RNA polymerase in overcoming lesions, CSA’s detailed role in repair has so far remained elusive. CSA is part of the DDB1-CSA-Cul4-Rbx1 E3 ubiquitin ligase complex. The available data suggest that CSA may function as a substrate adaptor for ubiquitination by the DDB1-Cul4-Rbx1 ligase. I will pursue a novel structure-driven proteomic approach to identify the substrate epitope recognized by the DDB1-CSA-Cul4-Rbx1 E3 ubiquitin ligase. These experiments aim to provide the important missing signal required for recruitment of the ligase complex to sites of stalled RNA polII complexes. Importantly, the CSA ligase, as it arrives at sites of DNA damage, is inactive. Our comprehensive structural and biochemical efforts will thus include the mechanisms of regulation of the CSA ubiquitin ligase activity by activators and inhibitors following recruitment to the repair site. MoBa-CS will not only improve our understanding of CSA’s molecular role in Cockayne syndrome, but also reveal CSA’s mode of action within the essential transcription coupled repair pathway. Understanding the cellular signals overseeing transcription coupled repair will provide important insights into how the pathway is integrated within the overall DNA damage response circuitry of the cell. ERC funding would enable us to pursue an interdisciplinary proteomic and structure based approach in examining DDB1-CSA function.

Keywords: dna repair,nucleotide excision repair,cockayne syndrome,ubiquitin transferases,macromolecular complexes,crystallography,proteomics
Decoding genetic switches in T helper cell differentiation (THSWITCH)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Genetics,Genomics,Bioinformatics and Systems Biology
Countries involved: Germany,United Kingdom
Call:  (ERC-2010-StG_20091118, 2010)
Start date: 2011-01-01
End date: 2015-12-31
Duration (months): 60.0
Total project cost (EUR): 1330634.0
EU funding (EUR): 1330634.0
Participants: 2
Project status: CLOSED

The central question of this proposal is: how are changes in cell state regulated at the transcriptomic and epigenetic level? I will tackle this question using an integrated computational and experimental approach with the T helper cell system as my model. The Th system consists of a naïve precursor cell type, and four main differentiated cell types that have some capacity to interconvert, known as plasticity. The experiments will be designed to measure both entire transcriptomes and single mRNAs by single molecule RNA-FISH. (i) Quantifying genetic switches. On a genome-wide scale, what is the distribution of gene expression levels in the Th cell types? Do genes have two discrete expression levels (on and off) in terms of mRNAs per cell or a continuous distribution of expression levels? How do epigenetic marks correlate with expression levels? We will use genome-wide RNA-seq and epigenetic ChIP-seq experiments on homogeneous populations of cells coupled with new computational methods. (ii) The molecular nature of the genetic switch. What is the hierarchy and kinetics of molecular events that drive gene expression changes during differentiation and plasticity? Using highly resolved timecourse experiments to profile individual cell generations, we will unravel the temporal order of regulation by transcription factors, microRNAs and epigenetic factors using RNA-seq and ChIP-seq experiments. We will integrate the data computationally to infer new regulatory interactions. (iii) How genetic switches drive cell type switches. Which transcription factors directly regulate cytokines, the phenotypic readout of Th cells? Are the kinetics of these interactions graded or switch-like? What is the extent of stochastic cell-to-cell variation? We will validate predicted transcription factor-cytokine interactions and quantify levels of proteins and mRNA in single cells with fluorescence microscopy experiments, modelling this data probabilistically.

Keywords: differentiation,immunology,plasticity
International Data Exchange and Data Representation Standards for Proteomics (PROTEOMEXCHANGE)

Framework: FP7 — Cooperation
Programme: Health
Destination: Translating research for human health
Action type: Coordination and support actions
Countries involved: Germany,United Kingdom,Belgium,Switzerland,United States,Germany,Germany,Spain,Spain,Spain
Call:  (FP7-HEALTH-2010-single-stage, 2010)
Start date: 2011-01-01
End date: 2014-06-30
Duration (months): 42.0
Total project cost (EUR): 2201655.2
EU funding (EUR): 1925962.0
Participants: 13
Project status: CLOSED

Over the last few years the field of proteomics has evolved into a prolific data producer. As a result, various databases that collect and redistribute the acquired data have been established. While data format standards for quantitative proteomics have now been defined and implemented with significant contribution from the recently completed EU ProDaC grant, standards for quantitative proteomics are still lacking. This simultaneous creation of multiple repositories and databases, and lack of standards for quantitative proteomics result in a fragmentation of data, and cause confusion for data submitters and users alike. Based on consortium expertise in the operation of large scale proteomics repositories (PRIDE, PeptideAtlas, Tranche, Peptidome) we aim to implement the next step, regular data exchange between major international proteomics resources. In parallel, we will further develop standards (mzQuantML) for the dynamic field of quantitative mass spectrometry. The main objectives of ProteomExchange are user-oriented: (i) to provide a single point of data submission to the user; (ii) to ensure data availability in all of the different member databases; (iii) to use community standard formats to represent the data, so it becomes accessible to all regardless of data origin; (iv) to provide added value through different views on the same data, from repositories to derived search tools. With an international consortium and support from large scale data producers (ISAS (Germany), U. Cambridge (UK), Karolinska Institute (Sweden)), industry (Pfizer, Philips, Waters), and journals (Nature Biotechnology, MCP, JPR), we here propose a Coordination Action project to solidify an emerging informal collaboration between major repositories into a production-quality data deposition and dissemination consortium on par with the systems so successfully employed by three-dimensional structure databases and nucleotide sequence databases, amongst others.

Keywords: standards development,proteomics,data deposition,mass spectrometry
Targeting Multidrug Resistant Cancer (ABC)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Diagnostic tools, therapies and public health
Countries involved: Hungary
Call:  (ERC-2010-StG_20091118, 2010)
Start date: 2012-01-01
End date: 2016-12-31
Duration (months): 60.0
Total project cost (EUR): 1499640.0
EU funding (EUR): 1499640.0
Participants: 1
Project status: CLOSED

Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations: - First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37); - Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells (Turk et al.,Cancer Res, 2009. 69(21)); - Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15); - Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204). I propose a comprehensive series of studies that will address thefollowing critical questions: - First, what is the scope of MDR-selective compounds? - Second, what is their mechanism of action? - Third, what is the optimal therapeutic modality? Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.

Keywords: drug resistance,p-glycoprotein,abc transporters
Molecular mechanisms controlling X chromosome inactivation (ACTIVATION OF XCI)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Genetics,Genomics,Bioinformatics and Systems Biology
Countries involved: Netherlands
Call:  (ERC-2010-StG_20091118, 2010)
Start date: 2011-04-01
End date: 2016-03-31
Duration (months): 60.0
Total project cost (EUR): 1500000.0
EU funding (EUR): 1500000.0
Participants: 1
Project status: CLOSED

In mammals, gene dosage of X-chromosomal genes is equalized between sexes by random inactivation of either one of the two X chromosomes in female cells. In the initial phase of X chromosome inactivation (XCI), a counting and initiation process determines the number of X chromosomes per nucleus, and elects the future inactive X chromosome (Xi). Xist is an X-encoded gene that plays a crucial role in the XCI process. At the start of XCI Xist expression is up-regulated and Xist RNA accumulates on the future Xi thereby initiating silencing in cis. Recent work performed in my laboratory indicates that the counting and initiation process is directed by a stochastic mechanism, in which each X chromosome has an independent probability to be inactivated. We also found that this probability is determined by the X:ploïdy ratio. These results indicated the presence of at least one X-linked activator of XCI. With a BAC screen we recently identified X-encoded RNF12 to be a dose-dependent activator of XCI. Expression of RNF12 correlates with Xist expression, and a heterozygous deletion of Rnf12 results in a marked loss of XCI in female cells. The presence of a small proportion of cells that still initiate XCI, in Rnf12+/- cells, also indicated that more XCI-activators are involved in XCI. Here, we propose to investigate the molecular mechanism by which RNF12 activates XCI in mouse and human, and to search for additional XCI-activators. We will also attempt to establish the role of different inhibitors of XCI, including CTCF and the pluripotency factors OCT4, SOX2 and NANOG. We anticipate that these studies will significantly advance our understanding of XCI mechanisms, which is highly relevant for a better insight in the manifestation of X-linked diseases that are affected by XCI.

Keywords: x chromosome inactivation,rnf12,stochastic,xist
The piRNA pathway in the Drosophila germline a small RNA based genome immune system (DROSOPIRNAS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Cellular and Developmental Biology
Countries involved: Austria
Call:  (ERC-2010-StG_20091118, 2010)
Start date: 2010-09-01
End date: 2015-08-31
Duration (months): 60.0
Total project cost (EUR): 1500000.0
EU funding (EUR): 1500000.0
Participants: 1
Project status: CLOSED

The discovery of RNA interference (RNAi) has revolutionized biology. As a technology it opened up new experimental and therapeutic avenues. As a biological phenomenon it changed our view on a diverse array of cellular processes. Among those are the control of gene expression, the suppression of viral replication, the formation of heterochromatin and the protection of the genome against selfish genetic elements such as transposons. I propose to study the molecular mechanism and the biological impact of a recently discovered RNAi pathway, the Piwi interacting RNA pathway (piRNA pathway). The piRNA pathway is an evolutionarily conserved small RNA pathway acting in the animal germline. It is the key genome surveillance system that suppresses the activity of transposons. Recent work has provided a conceptual framework for this pathway: According to this, the genome stores transposon sequences in heterochromatic loci called piRNA clusters. These provide the RNA substrates for the biogenesis of 23-29 nt long piRNAs. An amplification cycle steers piRNA production predominantly to those cluster regions that are complementary to transposons being active at a given time. Finally, piRNAs guide a protein complex centered on Piwi-proteins to complementary transposon RNAs in the cell, leading to their silencing. In contrast to other RNAi pathways, the mechanistic framework of the piRNA pathway is largely unknown. Moreover, the spectrum of biological processes impacted by it is only poorly understood. piRNAs are for example not only derived from transposon sequences but also from various other genomic repeats that are enriched at telomeres and in heterochromatin. We will systematically dissect the piRNA pathway regarding its molecular architecture as well as its biological functions in Drosophila. Our studies will be a combination of fly genetics, proteomics and genomics approaches. Throughout we aim at linking our results back to the underlying biology of germline development.

Keywords: drosophila genetics,piwi-pathway,rna interference,transposon control,germline development
Initiating and interfering with silencing of transposons (I2ST)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Genetics,Genomics,Bioinformatics and Systems Biology
Countries involved: France
Call:  (ERC-2010-StG_20091118, 2010)
Start date: 2010-10-01
End date: 2015-09-30
Duration (months): 60.0
Total project cost (EUR): 1490876.0
EU funding (EUR): 1490876.0
Participants: 1
Project status: CLOSED

There is no living organism that does not contain transposons, and they make up a significant fraction, and in some instances, the vast majority of the genome in a given species. Owing to their proliferation propensity, these mobile genetic elements can create genetic variability providing selective benefits, but they also have a mutagenic potential. Therefore, host genomes have evolved epigenetic surveillance mechanisms to recognize and silence transposons. If maintenance of silencing is rather well understood, little is know about how the host recognize transposons as non-self elements and initiate silencing as they invade the genome. Also, although several examples indicate that a variety of environmental factors can reverse transposon silencing, how such factors interfere with the silencing machinery is largely unknown. The proposed research project will make use of our recent discovery of active endogenous retrotransposons in Arabidopsis to decipher genetically the mechanisms involved in initiating silencing of a transposon. In parallel, we will characterize how DNA-methylation associated silencing can be efficiently re-established once it has been lost, and use a genome-wide approach to determine the extent of this phenomenon. Finally, we intend to determine the genome-wide impact of a stress on transposon silencing and to genetically identify and characterize the molecular bases of stress-induced release of silencing at transposons. Our studies have the potential to bring general insights into how transposons have been so successful in colonizing host genomes, how they are kept under tight control and can be unleashed thereby contributing to genome plasticity and environmental adaptation.

Keywords: retrotransposon,silencing,dna methylation,stress