Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Mitochondrial membrane organization by protein scaffolds and lipid dynamics (MITOSCAFFOLD)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Cellular and Developmental Biology
Countries involved: Germany
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-04-01
End date: 2014-12-31
Duration (months): 69.0
Total project cost (EUR): 1878000.0
EU funding (EUR): 1878000.0
Participants: 1
Project status: CLOSED

Biological membranes are complex structures built up of a multiplicity of membrane lipids and proteins controlling essential cellular processes. This is exemplified by mitochondria, dynamic double-membrane bound organelles, with essential roles in diverse metabolic and cellular signalling pathways. The mitochondrial inner membrane is considered to be the protein richest cellular membrane, whose functional impairment is associated with aging, myopathies and diverse neurological disorders in human. Recent evidence from our group revealed essential roles of large, ring-like prohibitin complexes in the inner membrane for embryonic development in mice, cell proliferation, resistance against apoptosis, and the maintenance of mitochondrial cristae. Prohibitins comprise a conserved and ubiquitously expressed protein family and are suggested to serve as protein scaffolds in the inner membrane. Defining the network of genetic interactions in yeast, we could establish that prohibitin function depends on the supply of the non-bilayer phospholipids cardiolipin and phosphatidyl ethanolamine and on intramitochondrial lipid trafficking. These findings indicate that mitochondrial function and ultrastructure requires a defined spatial organization of the inner membrane, which is maintained by a defined lipid composition and prohibitins serving as protein scaffolds. Here, we propose a comprehensive analysis of the function of prohibitins and of novel components involved in mitochondrial lipid trafficking and phospholipid biosynthetic pathways. These studies will include genetic as well as biochemical and proteomic approaches and employ both yeast and murine models to integrate the molecular understanding of functionally conserved processes into the physiological context. As components of this system have been linked to cardiomyopathies and diverse neurological disorders, our studies are likely to provide new insight into pathomechanisms of human disease.

Keywords: mitochondria,mitochondrial dynamics,lipid transport,membrane scaffold,prohibitin,cardiolipin
Switching the structure-function relationship of proteins by mechanical forces: physiological and technological implications (MECHANOCHEM SWITCHES)

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: Switzerland
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-04-01
End date: 2014-03-31
Duration (months): 60.0
Total project cost (EUR): 2499990.0
EU funding (EUR): 2499990.0
Participants: 1
Project status: CLOSED

After a decade of new insights into single molecule mechanics, my key interests are now directed towards asking how (a) mechanical forces can alter the structure-function relationship of proteins and (b) whether such force-regulated structural alterations are of physiological significance. Since forces are applied by cells via the transmembrane integrin junctions to the extracellular matrix, my goal is to decipher how the extracellular matrix protein fibronectin, integrins, and cytoplasmic scaffolding proteins that link integrins to the cytoskeleton are functionally regulated by force. Using high performance computational approaches, we will derive with Angstrom precision how their structures are changed when stretched using Molecular (MD) and Steered Molecular Dynamics (SMD). Knowledge how tensile forces alter the structure of proteins is central to develop experimentally testable mechanisms how force might regulate various functions. Experimentally, we will first address how the many different functions of fibronectin are regulated by force. This will involve quantitative studies how the interaction of fibronectin fibers with various serum proteins and growth factors is altered when mechanically strained. Preliminary studies show already that the strain-dependent binding can vary greatly among different serum proteins. We will then investigate whether the stretching and unfolding of extracellular matrix proteins co-regulates cell phenotypes. Finally, understanding the principles of mechanotransduction is not only crucial to gain far deeper insight into how cells work, but new technologies might be derived from these novel insights. Our longer-range goals are thus to develop new technologies that exploit proteins as mechanically regulated switches, from the design and screening of drugs that target mechanically strain proteins, to deriving new design principles how to better engineer tissue scaffolds that exploit mechano-regulated cell-matrix interactions.

Keywords: biophysics of single molecule mechanics,force-regulated molecular interactions,mechano-chemical signal conversion,cell signaling,mechanotransduction,tissue engineering,mechnosensitive drugs
Cardiac Death and Regeneration (CADRE)

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: United Kingdom
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-01-01
End date: 2013-12-31
Duration (months): 60.0
Total project cost (EUR): 2497576.0
EU funding (EUR): 2497576.0
Participants: 1
Project status: CLOSED

Cardiac muscle death, unmatched by muscle cell creation, is the hallmark of acute myocardial infarction and chronic cardiomyopathies. The notion of heart failure as a muscle-cell deficiency disease has driven interest worldwide in ways to increase heart muscle cell number, by over-riding cell cycle constraints, suppressing cell death, or, most directly, cell grafting. Using stem cell antigen-1, we previously identified telomerase-expressing cells in adult mouse myocardium, which have salutary properties for bona fide cardiac regeneration. Here, we seek to address systematically the mechanisms for long-term self-renewal in Sca-1+ adult cardiac progenitor cells and in the smaller side population fraction, which is clonogenic and expresses telomerase at even higher levels. Specifically, we propose to study the roles of telomerase and of the telomere-capping protein, TRF2. Aim 1, Determine the properties of adult cardiac progenitor cells in mice that lack the RNA component of telomerase (TERC). Aim 2, Determine the properties of adult cardiac progenitor cells in mice that lack the catalytic component (TERT). To distinguish between effects of these two gene products themselves versus those that depend on cumulative telomere dysfunction, G2- and G5-null mice will be compared. Aim 3, Determine the properties of adult cardiac muscle and adult cardiac progenitor cells that lack the telomere-capping protein TRF2. Aim 4, Test the prediction that forced expression of TERT and TRF2 can augment cardiac muscle engraftment in vivo and enhance the clonal derivation of adult cardiac progenitor cells in vitro, without adversely affecting the cells differentiation potential. Work proposed in Aims 1-3 would provide indispensable fundamental information about the function of endogenous telomerase in adult cardiac progenitor cells. Conversely, work in Aim 4 would test potential therapeutic implications of telomerase and a telomere-capping protein with this auspicious population.

Keywords: cardiac,heart,heart failure,myocardial infarction,myocardium,regeneration,stem cell antigen-1,side population,telomerase
Next Generation in-vivo imaging platform for post-genome biology and medicine (MSOT)

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: Germany,Germany
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-03-01
End date: 2014-06-30
Duration (months): 64.0
Total project cost (EUR): 1999992.0
EU funding (EUR): 1999992.0
Participants: 2
Project status: CLOSED

With re-defined challenges in post-genome biology and medicine related to understanding the regulation and function of genes, proteins and multi-factorial disease, the development of accelerated and quantitative in-vivo observation of functional -omics at different system levels becomes a vital target. This proposal offers to develop therefore a next-generation biomedical imaging platform, designed to radically impact biomedical and drug discovery applications. The imaging strategy aims at resolving powerful optical reporters (fluorescent proteins, nanoparticles, optical probes) with 10-100 micron resolution and femptomole sensitivity through several millimeters to centimeters of tissue. This performance brings unprecedented ability to non-invasively visualize biological and molecular processes in-vivo in intact organisms over time. To achieve these goals, the proposal considers first the development of multi-spectral opto-acoustic tomography (MSOT) as a high performance method for revolutionizing biomedical imaging. Then, the proposal offers to develop powerful application areas in visualizing functional –omics, disease growth and drug effectiveness. The advancements offered herein can become a highly preferred biomedical imaging modality while offering ground-breaking imaging performance, safe non-ionizing radiation, an easy to disseminate platform, and unparalleled flexibility in capitalizing on powerful optical contrast using molecular reporters.

Keywords: molecular imaging,functional genomics,proteomics,drug discovery,clinical imaging
Novel Systematic Strategies for Elucidating Cellular Regulatory Circuits (REGULATORYCIRCUITS)

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: Israel
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-01-01
End date: 2013-12-31
Duration (months): 60.0
Total project cost (EUR): 2199899.0
EU funding (EUR): 2199899.0
Participants: 1
Project status: CLOSED

The precise regulation of gene expression has been the subject of extensive scrutiny. Nonetheless, there is a big gap between genomic characterization of transcriptional responses and our predictions based on known molecular mechanisms and networks and of transcription regulation. In this proposal I argue for an approach to bridge this gap by using a novel experimental strategy that exploits the recent maturation of two technologies: the use of fluorescence reporter techniques to monitor promoter activity and high-throughput genetic manipulations for the construction of combinatorial genetic perturbations. By combining these, we will screen for genes that modulate the transcriptional response of target promoters, use genetic interactions between them to better resolve their functional dependencies, and build detailed quantitative models of transcriptional processes. We will use the budding yeast model organism, which allows for efficient manipulations, to dissect two transcriptional responses that are prototypical of many regulatory networks in living cells: [1] The early response to osmotic stress, which is mediated by at least two signaling pathways and multiple transcription factors, and [2] the central carbon metabolism response to shifts in carbon source, which involves multiple sensing and signaling pathways to maintain homeostasis. Our approach will elucidate mechanisms that are opaque to classical screens and facilitate building detailed predictive models of these responses. These results will lead to understanding of general principles that govern transcriptional networks. This is the first approach to comprehensively characterize the molecular mechanisms that modulate a transcriptional response, and arrange them in a coherent network. It will open many questions for detailed biochemical investigations, as well as set the stage to extend these ideas to use more detailed phenotypic assays and in more complex organisms.

Keywords: regulatory networks,genetic interaction maps
Evolution of Development In Plants (EDIP)

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: United Kingdom
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-07-01
End date: 2015-06-30
Duration (months): 72.0
Total project cost (EUR): 2230732.0
EU funding (EUR): 2230732.0
Participants: 1
Project status: CLOSED

Different morphologies evolve in different organisms in response to changing environments. As land plants evolved, developmental mechanisms were either generated de novo, or were recruited from existing toolkits and adapted to facilitate changes in form. Some of these changes occurred once, others on multiple occasions, and others were gained and then subsequently lost in a subset of lineages. Why have certain forms survived and others not? Why does a fern look different from a flowering plant, and why should developmental biologists care? By determining how many different ways there are to generate a particular morphology, we gain an understanding of whether a particular transition is constrained. This basic information allows an assessment of the extent to which genetic variation can modify developmental mechanisms and an indication of the degree of developmental plasticity that is possible and/or tolerated both within and between species. This proposal aims to characterize the developmental mechanisms that underpin the diverse shoot forms seen in extant plant species. The main goal is to compare developmental mechanisms that operate in vegetative shoots of bryophytes, lycophytes, ferns and angiosperms, with a view to understanding the constraints that limit morphological variation. Specifically, we will investigate the developmental basis of three major innovations that altered the morphology of vegetative shoots during land plant evolution: 1) formation of a multi-cellular embryo; 2) organization of apical growth centres and 3) patterning of leaves in distinct spatial arrangements along the shoot. To facilitate progress we also aim to develop transgenic methods, create mutant populations and generate digital transcriptomes for model species at key phylogenetic nodes. The proposed work will generate scenarios to explain how land plant form evolved and perhaps more importantly, how it could change in the future.

Keywords: evo/devo
"Endosomal trafficking during morphogenetic signaling and asymmetric cell division" (SARA)

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: Switzerland
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-05-01
End date: 2014-04-30
Duration (months): 60.0
Total project cost (EUR): 2287785.0
EU funding (EUR): 2287785.0
Participants: 1
Project status: CLOSED

We plan to study the mechanism that controls the growth of animal tissues. We will focus on two types of mitotic modes: asymmetric cell divisions and the morphogen-dependent proliferation of developing cells. Our recent work has shown that endosomal trafficking plays key roles during asymmetric division and during the formation of morphogen gradients. We therefore plan to unravel the biochemical and cell biological mechanisms underlying the key role of endosomes during growth control using Drosophila as a model system and validating it in the Zebrafish, where we will also discover the new endosomal properties that emerged in vertebrates. Our project will pursue two aims: 1. to discover the key lipids and proteins involved in the endosome-mediated control of growth; 2. to study at the biophysical level the signaling and membrane trafficking events that, emanating from the endosomes, mediate the control of growth. We have already shown that endosomal trafficking is essential during the formation of morphogen gradients and asymmetric cell division. This proposal ultimately aims at the physical, molecular and cellular mechanisms behind.

Keywords: biophysics lipidomics asymmetric cell division morphogen gradients growth control
COMMOM MECHANISMS UNDERLYING CANCER AND AGEING (CANCER&AGEING)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Molecular and Structural Biology and Biochemistry
Countries involved: Spain
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-04-01
End date: 2015-03-31
Duration (months): 72.0
Total project cost (EUR): 2000000.0
EU funding (EUR): 2000000.0
Participants: 1
Project status: CLOSED

In recent years, we have made significant contributions to the understanding of the tumour suppressors p53, p16INK4a, and ARF, particularly in relation with cellular senescence and aging. The current project is motivated by two hypothesis: 1) that the INK4/ARF locus is a sensor of epigenetic damage and this is at the basis of its activation by oncogenes and aging; and, 2) that the accumulation of cellular damage and stress is at the basis of both cancer and aging, and consequently "anti-damage genes", such as tumour suppressors, simultaneously counteract both cancer and aging. With regard to the INK4/ARF locus, the project includes: 1.1) the generation of null mice for the Regulatory Domain (RD) thought to be essential for the proper regulation of the locus; 1.2) the study of the INK4/ARF anti-sense transcription and its importance for the assembly of Polycomb repressive complexes; 1.3) the generation of mice carrying the human INK4/ARF locus to analyze, among other aspects, whether the known differences between the human and murine loci are "locus autonomous"; and, 1.4) to analyze the INK4/ARF locus in the process of epigenetic reprogramming both from ES cells to differentiated cells and, conversely, from differentiated cells to induced-pluripotent stem (iPS) cells. With regard to the impact of "anti-damage genes" on cancer and aging, the project includes: 2.1) the analysis of the aging of super-INK4/ARF mice and super-p53 mice; 2.2) we have generated super-PTEN mice and we will examine whether PTEN not only confers cancer resistance but also anti-aging activity; and, finally, 2.3) we have generated super-SIRT1 mice, which is among the best-characterized anti-aging genes in non-mammalian model systems (where it is named Sir2) involved in protection from metabolic damage, and we will study the cancer and aging of these mice. Together, this project will significantly advance our understanding of the molecular mechanisms underlying cancer and aging.

Keywords: tumour suppression,senescence,p16,p53,arf,cell cycle regulators
Targeting Receptors Of Jointly Assembled Ligand-Drug Constructs (TROJA)

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: Denmark
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-04-01
End date: 2014-03-31
Duration (months): 60.0
Total project cost (EUR): 2400000.0
EU funding (EUR): 2400000.0
Participants: 1
Project status: CLOSED

The TROJA proposal is an investigative bioengineering study of the exploitation of specific endocytic receptors for targeting small molecule drugs to specific cells in order to improve medical therapy. This is a new approach with scientific roots in the basic research on endocytic receptors and protein expression carried out in the laboratory of the applicant. The major line of the proposal concerns the construction of combinatory drugs for targeting the haptoglobin (Hp)-hemoglobin receptor CD163 (Kristiansen et al., Nature 409:198-201) expressed in the monocyte-macrophage system. The platform may apply to a broad spectrum of diseases such as inflammatory diseases, various infections and certain cancers which all have CD163-expressing macrophages or malignant derivatives as key cell type in the pathogenesis of the disease. Dependent of the above-mentioned diseases to be treated, the drugs are intended to have anti-inflammatory, microbiotic or cytostatic effects. Efficacy of the combinatory drug will be investigated in monocytes/macrophages, CD163-transfected cells and as well as in suitable animal models including transgenic animals. Another and minor line of the proposal concerns the construction of combinatory drugs for targeting a very recently discovered Hp-Hb receptor expressed in trypanosomes (Vanhollebeke et al., Science, in press) causing sleeping sickness. Both lines of this research proposal will take advantage of established recombinant protein expression methods and chemical coupling technology to construct jointly assembled ligand-drugs complexes. In terms of drug efficacy and toxicity, the aim is to design combinatory products that remain largely inactive in their receptor-binding form, but upon release in the cells or parasites the active small molecule components become active. The discovery of such a Trojan horse platform for cellular drug entry may have major implications for future drug development and for new applications of existent drugs.

Keywords: receptors,congugate,drug-delivery,macrophage,biofunctional