Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Interaction between the protein repair enzyme L-isoaspartyl methyltransferase and insulin/IGF-1 signaling in mice and worms (PIMT AND SIGNALING)

Framework: FP7 — People
Programme: Marie-Curie Actions
Theme: Marie Skłodowska-Curie
Destination: International Re-integration Grants
Action type: Support for training and career development of researchers (Marie Curie)
Countries involved: Luxembourg,Belgium
Call:  (FP7-PEOPLE-2010-RG, 2010)
Start date: 2011-04-01
End date: 2015-03-31
Duration (months): 48.0
Total project cost (EUR): 100000.0
EU funding (EUR): 100000.0
Participants: 2
Project status: CLOSED

The protein L-isoaspartyl methyltransferase (PIMT) is well known for its protein repair function, namely the reconversion of deamidated and/or isomerized asparaginyl and aspartyl residues (L-isoaspartyl residues) into their normal, non-isomerized forms. The conversion of biomolecules to non-useful and potentially toxic products by unwanted chemical reactions represents probably an important aspect of the aging process in living organisms. To the extent that they can minimize the accumulation of damaged molecules, they can endure. PIMT knockout mice accumulate high levels of damaged proteins in their tissues, especially the brain, and die of massive seizures at an average age of 42 days. On the other hand, worms and flies overexpressing this enzyme live longer, strongly suggesting a role for PIMT in the aging process. A particularly intriguing observation is that the insulin/IGF-1 signaling pathway is activated in the brain of PIMT knockout mice. Genetic evidence also exists for an interaction between PIMT and insulin-like signaling in Caenorhabditis elegans. It has recently become clear that insulin-like signaling plays an important role in the regulation of the aging process. Lowered insulin/IGF-1 signaling, especially in neuronal tissues, leads to lifespan extension in worms, flies and mice. The overall objective of this project is to understand the link between PIMT and insulin-like signaling. A first aim is to consolidate the interaction between PIMT and insulin-like signaling in worms. A second aim is to analyze the effect of PIMT deficiency on the phosphoproteome of mouse brains. A third aim is to elucidate the mechanism by which PIMT deficiency leads to the observed changes in protein phosphorylation. Several routes, including direct regulation of protein phosphatase activity by PIMT methylation, modulation of such an activity by a critical isoaspartyl residue, and effect of high isoaspartyl content in a protein on its phosphorylation state will be explored.

Keywords: isoaspartyl methyltransferase,protein repair,insulin signaling,protein phosphorylation,protein carboxyl methylation,aging process,caenorhabditis elegans
MicroRNA Networks in Neuronal Development and Plasticity (NEURO-MIR-NETWORKS)

Framework: FP7 — People
Programme: Marie-Curie Actions
Theme: Marie Skłodowska-Curie
Destination: International Re-integration Grants
Action type: Support for training and career development of researchers (Marie Curie)
Countries involved: Netherlands
Call:  (FP7-PEOPLE-2010-RG, 2010)
Start date: 2011-03-01
End date: 2015-02-28
Duration (months): 48.0
Total project cost (EUR): 100000.0
EU funding (EUR): 100000.0
Participants: 1
Project status: CLOSED

microRNAs (miRNAs) are novel gene circuitry regulators with an elusive role in neuronal development and plasticity. These small non-coding RNA molecules may explain some of the dysfunctional mechanisms in mental disorders, and are promising targets for diagnosis and treatment of neuropsychiatric disorders. I have recently identified pre-synaptically enriched miRNAs, of which miR-338 was found to modulate the mitochondrial function. This fellowship will allow me to use the knowledge I have gained on the roles of synaptic translation in neuronal development and plasticity as a Research Associate in USA and implement that knowledge to Europe. The three main objectives of my proposed research are: (1) to identify candidate miRNAs differentially expressed during hippocampal development and plasticity; (2) to delineate miRNA’s regulatory role on local protein synthesis which is required for synaptic plasticity; and (3) to determine the functions of miRNAs in neuronal development and plasticity. To address objectives 1 and 2, I will employ deep-sequencing to identify miRNA genes differentially and spatially expressed during experience-dependent synaptic plasticity in the rat hippocampus and its synaptic compartments, respectively, and carry out computational prediction followed by experimental confirmations to identify miRNAs involved in synaptic function. In objective 3, I will investigate miRNA function in different forms of synaptic plasticity using cell biological approaches combined with in vivo behavioral experiments. I anticipate that my interdisciplinary research approach will define the role of miRNAs in synaptic plasticity and memory storage. The research proposed is innovative and significant because it may establish a new avenue of research on synaptic pathophysiology in mental disorders, and may provide the European society with cutting-edge technology with the potential to generate new miRNA-based therapies to treat nervous system disorders.

Keywords: learning and memory,mental disorders,local protein synthesis,hippocampus,rna interference,neurodevelopment,axons,dendrites
Quantitative analysis of the interplay between cellular signaling and cell morphology during development (MORPHO-SIGNALING)

Framework: FP7 — People
Programme: Marie-Curie Actions
Theme: Marie Skłodowska-Curie
Destination: International Re-integration Grants
Action type: Support for training and career development of researchers (Marie Curie)
Countries involved: Israel
Call:  (FP7-PEOPLE-2010-RG, 2010)
Start date: 2011-03-01
End date: 2015-02-28
Duration (months): 48.0
Total project cost (EUR): 100000.0
EU funding (EUR): 100000.0
Participants: 1
Project status: CLOSED

During development, cells differentiate into well defined patterns through an orchestrated program in space and time. This differentiation into different cell states is coordinated by intercellular signaling and is interpreted via intracellular genetic circuits. However, many developmental processes also involve changes in cell morphology that occur concurrently with the differentiation process. How such morphological changes affect intercellular signaling? How cell morphology changes are controlled by intercellular signaling? And how the dynamic interplay between intercellular signaling, intracellular genetic circuits and regulation of cellular morphology generate the observed differentiation patterns? We will address these questions in the context of the Notch signaling pathway and Notch dependent pattern formation processes. Using a combination of micropatterning devices and quantitative time lapse microscopy, we will first measure the dependence of Notch signaling on the properties of the boundary between pairs of cells (e.g. length of boundary, molecular and mechanical properties). We will then use the information obtained from these measurements to construct mathematical models of Notch dependent pattern formation processes combining cell-cell signaling, intracellular circuitry and cell morphology in a unified manner. Such a combined experimental and theoretical approach will not only provide new insights into the Notch signaling pathway but will also provide a new framework for a whole class of developmental patterning processes involving morphological changes during differentiation.

Keywords: developmental biology,systems biology,notch signaling,cell morphology
Molecular imaging of the myocardium to facilitate cardiac stem cell therapy (STEM CELL IMAGING)

Framework: FP7 — People
Programme: Marie-Curie Actions
Theme: Marie Skłodowska-Curie
Destination: International Re-integration Grants
Action type: Support for training and career development of researchers (Marie Curie)
Countries involved: Germany
Call:  (FP7-PEOPLE-2010-RG, 2010)
Start date: 2011-07-01
End date: 2015-06-30
Duration (months): 48.0
Total project cost (EUR): 100000.0
EU funding (EUR): 100000.0
Participants: 1
Project status: CLOSED

In clinical trials, functional benefits of cell therapy for repair of the damaged heart have been moderate and variable. Frequently, only a small fraction of transplanted cells engrafts in injured myocardium. This limits therapeutic efficacy and may explain variability of results. There is a need for improved understanding of therapeutic mechanisms and for improved selection of candidates. Specific noninvasive imaging techniques, which go beyond assessment of structure and function of the heart, are promising new means for improving cell therapy. In this proposal, we aim at developing image-based strategies to facilitate stem cell engraftment. The myocardial microenvironment is considered to be a critical contributor to engraftment. It constitutes a suitable target for molecular imaging. Our central hypothesis is that molecular-targeted radionuclide imaging prior to cell delivery can characterize an optimal biologic environment which is supportive of cell engraftment after delivery, and thus predictive of successful myocardial regeneration. This hypothesis will be tested in 3 specific aims, using an array of noninvasive imaging techniques to characterize myocardial biology, to track stem cells and to determine functional and structural effects of cell delivery. Aim 1 will define the role of tissue perfusion and viability for successful engraftment of bone-marrow derived stem cells. Aim 2 will investigate the role of neurohumoral activation after ischemic damage for successful cardiac stem cell engraftment. And in aim 3, knowledge derived in a rat model in aims 1 and 2 will be translated to a large animal model and clinical camera systems. These studies will provide unique new insights into myocardial regeneration. They will also deliver imaging techniques for assistance in therapeutic decision making. The ultimate goal of the project is to optimize cell therapeutic benefit based on imaging of individual disease biology.

Keywords: health sciences,cardiology,nuclear medicine
Biological Invasions in Marine Ecosystems – the Role of Phenotypic Plasticity (ALIEN SPECIES)

Framework: FP7 — People
Programme: Marie-Curie Actions
Theme: Marie Skłodowska-Curie
Destination: European Re-integration Grants
Action type: Support for training and career development of researchers (Marie Curie)
Countries involved: Sweden
Call:  (FP7-PEOPLE-2010-RG, 2010)
Start date: 2011-04-01
End date: 2014-03-31
Duration (months): 36.0
Total project cost (EUR): 45000.0
EU funding (EUR): 45000.0
Participants: 1
Project status: CLOSED

In the era of the Evolutionary Synthesis, genetic recombination or mutation were assumed to create the raw material for evolution by natural selection. More recently, however, the genetic versus environmental basis of new selectable traits, and how genotype × environment interactions affect evolutionary trajectories, has risen to the forefront of evolutionary biology. Phenotypic plasticity [PP] is an individual’s inherent ability to change behaviour, physiology, morphology, or life-history in response to environmental cues. It is new to consider PP as a factor affecting biological invasion success and the process has virtually been ignored in marine environments. I intend to study PP, as the strategy can provide a mechanistic explanation to understand and predict successful invasions. Such knowledge is crucial since global invasions have significant impact on the ecology since invasive species creates genetic pollution and can change ecosystem functions. It has also a huge economic impact since estimated damage and control cost in the U.S. alone reach $138 billion annually. I will utilize common garden experiments as well as a molecular approach with cDNA microarry in order to assess the evolution of PP and study expressed genes, which administrate plasticity genes.

Keywords: aquatic biology,evolutionary biology,agricultural sciences,molecular genetics
Biosynthesis of very long-chain fatty acids in fish: Molecular and biochemical basis and implications in aquaculture (LONGFA)

Framework: FP7 — People
Programme: Marie-Curie Actions
Theme: Marie Skłodowska-Curie
Destination: European Re-integration Grants
Action type: Support for training and career development of researchers (Marie Curie)
Countries involved: Spain
Call:  (FP7-PEOPLE-2010-RG, 2010)
Start date: 2011-02-01
End date: 2014-01-31
Duration (months): 36.0
Total project cost (EUR): 45000.0
EU funding (EUR): 45000.0
Participants: 1
Project status: CLOSED

Recent investigations in mammals have suggest that very long-chain polyunsaturated fatty acids (VLC-PUFAs) can play pivotal roles in physiological processes including phototransduction in retina, fertility and spermatogenesis in testis, and brain functioning. In fish, however, VLC-PUFAs and their biosynthesis have escaped investigation despite many of the above functions have obvious interest in finfish aquaculture, where altered visual acuity (critical in visual predators such as most cultured fish species), fertility issues of broodstock, and disruptions of brain functioning can hinder normal development, and jeopardise the economical profit of the farm. The biosynthesis of VLC-PUFAs in mammals has been proposed to proceed through consecutive elongation reactions that enzymes called elongases of very long-chain fatty acids (Elovl) catalyse from PUFA substrates. Two members of the Elovl protein family, Elovl2 and Elovl4, have been found to mediate the production of VLC-PUFAs in target tissues. The objective of this proposal is to investigate the biosynthesis of VLC-PUFAs in finfish. Initially, the project will deal with objectives investigating basic molecular and biochemical aspects of the VLC- PUFA biosynthetic pathway. Then the project will proceed through more applied grounds exploring the potential impact that some aquaculture dietary strategies could have on VLC-PUFA biosynthesis. We plan to undertake this research using gilthead seabream Sparus aurata as a model, a teleost in which fatty acid metabolism has been previously investigated, and whose physiology is one of the best known among marine finfish species. Outcomes of the present project will be then transferred to other fish species and used to improve their production.

Keywords: nutrition (aquaculture),animal physiology,natural sciences,aquatic biology
Molecular Mechanisms of Neurodegeneration (RETROGRADE SIGNALING)

Framework: FP7 — People
Programme: Marie-Curie Actions
Theme: Marie Skłodowska-Curie
Destination: International Re-integration Grants
Action type: Support for training and career development of researchers (Marie Curie)
Countries involved: Israel
Call:  (FP7-PEOPLE-2010-RG, 2010)
Start date: 2011-03-01
End date: 2015-02-28
Duration (months): 48.0
Total project cost (EUR): 100000.0
EU funding (EUR): 100000.0
Participants: 1
Project status: CLOSED

Neuron cell death and synapse disruption seen during aging and in neurodegenerative diseases is a non-cell-autonomous process and involve a multi system progression. As neurons are highly polarized cells with very long axons, in order to remain healthy and function properly, they depend on accurate and efficient long-distance communication mechanisms. My long-term goal is to elucidate the molecular mechanisms for long distance signaling between neurons and their environment. I will combine state-of-the-art multidisciplinary approaches such as single molecule live imaging techniques, nanofluid-co-culture chambers and differential proteomics approaches on mouse model systems to address basic questions on the roles that retrograde signaling between muscle, glia and neurons play in cell survival and synapse stability. We will develop a unique in vitro microfluidic platform with motor neuron cell bodies on one-side and glia/muscle cells on the other side, which will allow us to distinguish local versus long distance signaling mechanisms and monitor retrograde axonal transport, as well as to manipulate retrograde signaling pathway regulating NMJ maintenance and cell survival. Three approaches will be taken: 1. In vitro and in vivo live cell imaging. 2. Specific cell biology. 3. Functional proteomics. Using model systems for aging and for neurodegenerative diseases will allow us to characterize the vital signaling mechanisms for NMJ/synapse maintenance and neuronal survival, as well as reveal novel stress factors that lead to nerve degeneration and cell death. Using the above strategies will provide a clearer picture of how cells use spatial localization and transport to regulate cell survival and synapse stability. The research will generate novel insights into neurodegenerative mechanisms and, ultimately, provide a molecular basis for new drugs as well as delivery methods to treat a range of neurodegenerative diseases.

Keywords: neuron,cell death,synapse,neurodegenerative diseases,als,long-distance signaling,glia,neuromuscular junction,axonal transport,gdnf,ncam,proteomics,dynein,live cell imaging,retrograde sig
Directed Evolution of Small-Molecule Cancer Therapeutics (DEVOCAT)

Framework: FP7 — People
Programme: Marie-Curie Actions
Theme: Marie Skłodowska-Curie
Destination: International Re-integration Grants
Action type: Support for training and career development of researchers (Marie Curie)
Countries involved: Greece
Call:  (FP7-PEOPLE-2010-RG, 2010)
Start date: 2011-05-01
End date: 2015-04-30
Duration (months): 48.0
Total project cost (EUR): 100000.0
EU funding (EUR): 100000.0
Participants: 1
Project status: CLOSED

Cancer imposes a tremendous socioeconomic burden in modern societies, causing ~1.7 million deaths in the EU annually. 15-20% of these cases occur due to mutations in the oncosuppressor gene p53, which destabilize the protein and inactivate its ability to mediate apoptosis under physiological conditions. Today, no drugs exist which can restore the function of mutant p53 and treat cancer. The present proposal deals with the discovery of potential cancer therapeutics of this type. The topic of the proposed research is the directed evolution of small molecules which can bind to and restore the folding and function of destabilized oncogenic variants of p53 (p53*). These compounds will be selected from libraries of small molecules which will be biosynthesized in microbial cells. Biosynthesis will be carried out using an approach that allows for facile preparation of a very large number of test compounds, which will exhibit high levels of chemical and structural diversity. These small-molecule libraries will then be screened and the compounds which can bind to and improve the folding of p53* will be identified using a high-throughput genetic screen. The effect of the identified compounds on the stability of p53* will be subsequently evaluated in vitro by using biochemical and biophysical methods of protein analysis, and their ability to revitalize apoptosis will be tested in selected human cancer cell lines. The compounds which will be found capable of restoring the stability and apoptosis-mediating function of p53* will become drug candidates against a broad panel of cancers.

Keywords: directed evolution,small molecule,cancer,p53,genetic screen,biosynthesis
New therapeutic targets for DM1: miRNAs analysis in DM1 disease models (DM1-MIRNA)

Framework: FP7 — People
Programme: Marie-Curie Actions
Theme: Marie Skłodowska-Curie
Destination: International Re-integration Grants
Action type: Support for training and career development of researchers (Marie Curie)
Countries involved: Spain
Call:  (FP7-PEOPLE-2010-RG, 2010)
Start date: 2011-07-01
End date: 2015-06-30
Duration (months): 48.0
Total project cost (EUR): 100000.0
EU funding (EUR): 100000.0
Participants: 1
Project status: CLOSED

Expansion of a non-coding CTG tract in the DMPK gene leads to myotonic dystrophy type 1 (DM1), a dominant autosomal condition clinically characterized by myotonia, muscle waste and heart conduction defects among other symptoms. Transcripts containing long CUG stretches are toxic to the cell by their ability to interfere with gene expression regulation at several levels. Chief molecular alterations are sequestration of MBNL1 and upregulation of CUG-BP1, both alternative splicing regulators, leading to the expression of improper mature proteins. Additional molecular alterations have been suggested to contribute to the elaboration of the disease. We propose that changes in the normal levels of specific miRNAs entail a novel mechanism for DM1. This is supported by recent reports that found miR-206 misregulated in DM1 muscle tissue. Our long term objective is to identify additional miRNA expression alterations and to evaluate their potential as therapeutic targets. To this end, we will make use of two animal models, Drosophila and mice, both transcribing long CTG tracts. First, using complementary approaches of next generation sequencing and commercial real time PCR arrays we will obtain the miRNA expression profile in control and toxic RNA conditions. Second, we will characterize the origin of specific miRNA expression alterations, being suggested misregulated biogenesis, stability loss or direct sequestration by CUG RNA, and will validate the clinical relevance of our findings in DM1 muscle samples. Third, miRNAs relevant to DM1 will be functionally analyzed following loss and gain of function approaches in cell culture and in model animals. Finally, we will evaluate the suppression of toxic CUG RNA phenotypes in DM1 model flies in which expression of altered miRNAs has been artificially restored to assess their potential as therapeutic targets. Although focused in the DM1 human disease, our studies may also lead to important findings in the biology of miRNAs.

Keywords: micrornas myotonic distrophy dm1 genic regulation ctg expansion massive sequencing drosophila
Singularities of Lie Group Actions in Geometry and Dynamics (SILGA)

Framework: FP7 — People
Programme: Marie-Curie Actions
Theme: Marie Skłodowska-Curie
Destination: European Re-integration Grants
Action type: Support for training and career development of researchers (Marie Curie)
Countries involved: Spain
Call:  (FP7-PEOPLE-2010-RG, 2010)
Start date: 2011-03-01
End date: 2014-02-28
Duration (months): 36.0
Total project cost (EUR): 45000.0
EU funding (EUR): 45000.0
Participants: 1
Project status: CLOSED

This project continues and advances the research lines of my past scientific activity, in the context of a reintegration to my home scientific community and the starting of a stable academic activity with a tenure track and a subsequent permanent position. The scientific part of the proposal is the investigation of the geometry of actions of Lie groups in several dynamical and geometrical contexts, with emphasis in their singularities, and is articulated in the following two sections: A. Reduction Theory. Following previous research by me and other groups, I will study the reduction theory for Dirac and generalized complex geometry from both the global and local point of view. This study is a natural continuation of previous research efforts about the reduction theory of symplectic and Poisson manifolds. The main novelty is that we will focus on reduction in the case when the group action presents singularities (fixed points) in Dirac and generalized complex geometry, which is a topic yet to be explored. B. The theory of Hamiltonian relative equilibria. In this section I intend to perform a complete reorganization of the theory of Hamiltonian relative equilibria, as well as to advance it. We will competely redesign the existing theory in a way specifically adapted to the various distinguishing features of symmetric Hamiltonian systems This is a big project started during my previous stage at the University of Manchester. We have substantially advanced this problem during that period, and we expect to have results with significant impact within the duration of this Reintegration Grant.

Keywords: mathematics,geometry,dynamics,symmetry,singularities,momentum maps,symplectic geometry,hamiltonian systems,reduction,physics