ERC FUNDED PROJECTS

CD8 T lymphocytes have a fundamental role in ensuring the control of different types of intracellular pathogens including bacteria, parasites and most viruses. This control may fail due to several reasons. The current aggressive anti-cancer therapies (or rarely certain congenital immune deficiencies) induce CD8 depletion. After bone-marrow transplantation, long time periods are required to ensure T cell reconstitution particularly in the adult. This long lag-time is due to the long-time periods required for hematopoietic precursors to generate T lymphocytes and to a thymus insufficiency in the adult. However, even when CD8 T cells are present CD8 immune responses are not always adequate. Certain chronic infections, as HIV, induce CD8 dysfunction and it is yet unclear how to generate efficient CD8 memory responses conferring adequate protection. To address these questions this project aims 1) To find strategies ensuring the rapid reconstitution of the peripheral and the gut CD8 T cell compartments a) by studying the mechanisms involved HSC division and T cell commitment; b) by isolating and characterizing progenitors we previously described that are T cell committed and able of an accelerated CD8 reconstitution c) by developing new strategies that may allow stable thymus transplantation and continuous thymus T cell generation. 2) To determine the mechanics associated to efficient CD8 memory generation a) by evaluating cellular modifications that ensure the efficient division and the remarkable accumulation and survival of CD8 T cells during the adequate immune responses as compared to inefficient responses b) by studying CD8 differentiation into effector and memory cells in both conditions. These studies will use original experiment mouse models we develop in the laboratory, that allow to address each of these aims. Besides state of the art methods, they will also apply unique very advanced approaches we introduced and are the sole laboratory to perform.

1 969 644 €

Start date: 2009-02-01, End date: 2014-05-31

The key objective of this project is to promote cleaner and more efficient combustion technologies through the development of theoretically grounded and more accurate chemical models. This is motivated by the fact that the current models which have been developed for the combustion of constituents of gasoline, kerosene, and diesel fuels do a reasonable job in predicting auto-ignition and flame propagation parameters, and the formation of the main regulated pollutants. However their success rate deteriorates sharply in the prediction of the formation of minor products (alkenes, dienes, aromatics, aldehydes) and soot nano-particles, which have a deleterious impact on both the environment and on human health. At the same time, despite an increasing emphasis in shifting from hydrocarbon fossil fuels to bio-fuels (particularly bioethanol and biodiesel), there is a great lack of chemical models for the combustion of oxygenated reactants. The main scientific focus will then be to enlarge and deepen the understanding of the reaction mechanisms and pathways associated with the combustion of an increased range of fuels (hydrocarbons and oxygenated compounds) and to elucidate the formation of a large number of hazardous minor pollutants. The core of the project is to describe at a fundamental level more accurately the reactive chemistry of minor pollutants within extensively validated detailed mechanisms for not only traditional fuels, but also innovative surrogates, describing the complex chemistry of new environmentally important bio-fuels. At the level of individual reactions rate constants, generalized rate constant classes and molecular data will be enhanced by using techniques based on quantum mechanics and on statistical mechanics. Experimental data for validation will be obtained in well defined laboratory reactors by using analytical methods of increased accuracy.

1 869 450 €

Start date: 2008-12-01, End date: 2013-11-30

The main goal of the proposed research is to investigate the possibility of allowing below-ground support systems to respond to strong seismic shaking by going beyond a number of thresholds that would conventionally imply failure and are today forbidden by codes. Such thresholds include : (a) sliding at the soil-foundation interface ; (b) separation and uplifting of a shallow foundation from the soils ; (c) mobilization of bearing capacity failure mechanism for shallow foundations ; (d) structural yielding of pile foundations ; (e) combination of some of the above. Whereas under static loading conditions a slight exceedance of such thresholds leads to failure, the oscillatory nature of seismic shaking will allow such exceedances for a short period of time, with perhaps no detrimental or irreparable consequences. The latter take the form of permanent foundation displacements, rotations, or injuries , which the designer will aspire to confine within rational limits. The motivation and the need for this research has come from : (i) observations of actual behaviour in a variety of earthquakes ; conspicuous examples : the permanent tilting , overturning, and often survival of numerous buildings on extremely soft soil in Adapazari during the Kocaeli 1999 earthquake ; (ii) the foundation design of a number of critical structures (e.g., major bridge pier, air control tower, tall monuments, elevated water tanks,) against large seismic actions ; the disproportionately large overturning moment and/or base shear force of such slender structures can hardly be faced with today s conventional foundation methods, (iii) the need to seismically retrofit and rehabilitate older structures and historical monuments; (iv) structural yielding of pile foundations is now detectable (thanks to technological advances), thus eliminating one of the reasons for avoiding it.

2 399 992 €

Start date: 2008-12-01, End date: 2013-10-31

The project is multi-disciplinary by character. It focuses upon socio-historical processes of the transformation and 'circulation' of educated and ruling elites in several uniquely composite (both multi-ethnic and multi-confessional) East European regional or national societies, having experienced a number of radical changes of social and political regime as well as state souvereignty in the first half of the 20th century. The historical scope of the study extends from post-feudalism to communism. Societies involved comprise Hungary, Slovakia, Transylvania, Voivodina in the Carpathian Basin, Latvia and Estonia in the Baltics. The study draws upon sociological survey methods applied to historically successive elite brackets in form of exhaustive or quasi-exhaustive computerized prosopographical data banks, based on standardized individual biographies of elite members (as permitted by mostly archival sources to be exploited). The main targets would include secondary school graduates, students and graduates of higher education, the main intellectual professions (like doctors and lawyers.), the political power elites as well as 'reputational elites' - those cited in biographical dictionaries. The information fed into our data banks help to clarify thanks to various procedures of multi-variate statistical schemes the contrasting socio-cultural selection and recruitment of elite members, their educational path from primary to higher education, their professional career, intellectual creativity as well as socio-political standing and orientation. This is the first time that large region- or country-wide elite clusters are submitted to systematic socio-historical analyses, covering simultaneously all or most markets of activity and self-assertion of educated clusters in a vast international and comparative perspective related to culturally composite societal formations.

771 628 €

Start date: 2009-01-01, End date: 2012-03-31

This project focuses on fluid flow in porous materials with evolving microstructure in the context of civil engineering applications and geomechanics. When the distribution of cracks and the distribution of pore size evolve in concrete and rocks, the influence on the permeability in the case of a single or a multiphase fluid flow needs some in depth investigation. A recent review of state of the art in modelling progressive mechanical breakdown and associated fluid flow in heterogeneous rock shows that little is known on the coupled effects between micro cracking and the intrinsic permeability of a solid phase. The present project intends to tackle this relationship between mechanical breakdown and associated fluid flow in the context of poromechanics extended to non local modelling. In particular, we will investigate how the internal length which plays a pivotal role at the inception and propagation of material failure may interact with the permeability, what enhanced Darcy-like relationship might be derived in order to apprehend such effects and how to model fluid flow in tight porous materials. The models will be extended to complex and multicomponent systems reproducing as closely as possible the behaviour of real fluids in order to understand and to describe the thermodynamical behaviour due to confinement such as modification of phase transitions and capillary condensation. The principal investigator of this project is a specialist in the field of continuum damage mechanics, failure due to strain and damage localisation. He has been the founder and among the major promoters of non local damage modelling, which is today a state of the art model in computational structural failure analyses. After a decade of research on durability problems for which he was elected at Institut Universitaire de France, his research interests recently turned toward petroleum engineering, the focus of the research team he joined two years ago at université de Pau.

1 490 200 €

Start date: 2008-12-01, End date: 2013-11-30

Polycomb group (PcG) and trithorax group (trxG) genes were discovered in Drosophila melanogaster as repressors and activators of Hox genes, a set of transcription factors that specify the antero-posterior axis of the body plan. PcG and trxG proteins form multimeric complexes that are required to maintain their expression state after the initial transcriptional regulators disappear from the embryo. Subsequent work led to a better understanding of their mechanisms of action. Moreover, PcG and trxG genes have also been identified in vertebrates, where they regulate Hox genes, they are involved in cell proliferation, stem cell identity and cancer, genomic imprinting in plants and mammals and X inactivation. PcG and trxG components form multimeric complexes. Some trxG and PcG components possess methyltransferase activities directed toward specific lysines of histone H3, whereas other trxG and PcG proteins interpret these histone marks. Recent studies have described the genomewide distribution of PcG proteins and of their related histone modification in Drosophila and other species. However, the PcG recruitment code to their target chromatin is still not understood, and the mechanism of PcG-mediated gene silencing is unclear. The formation of subnuclear silencing compartments might contribute to the stable repression of transcription. Drosophila PcG proteins have a speckled nuclear distribution and the number of these so-called PcG bodies is progressively reduced during development. We showed that multiple PREs can associate in the nucleus to enhance the strength of PcG-mediated silencing. However, we do not know how frequent is this clustering process and how important it is functionally at a genomewide level. Our project will tackle these questions by using a combination of genetics, developmental biology, cell biology, genomics and bioinformatic approaches, with the aim to gain an integrated understanding of the role of Polycomb and trithorax in biology

2 200 000 €

Start date: 2009-09-01, End date: 2015-08-31

Game theory has been very successful in shaping modern economic theory over the past fifty years. Yet, the solution concepts developed under the assumption of perfect rationality require a degree of cognitive sophistication on players part that need not be realistic. In this project, I wish to broaden the definitions of equilibrium concepts to take into account the cognitive limitations of players. Armed with these equilibrium concepts, I wish to revisit a number of classic economic applications of game theory and economics in the hope that the proposed approach enhances our economic understanding. I also wish to check whether the proposed concepts are confirmed experimentally. Specifically, the project will rely on three new solution concepts I have recently introduced: the limited foresight equilibrium (Jehiel, 1995) in which players are viewed as knowing only the evolution of moves over the next n periods, the analogy-based expectation equilibrium (Jehiel, 2005) in which players understand only the average behavioural strategy of their opponents over bundles of states, and the valuation equilibrium (Jehiel and Samet, 2007) in which players attach the same valuation to a bundle of moves (possibly corresponding to different decision nodes). In each case, I assume that players choose their strategy based on the simplest representation of their environment that is consistent with their partial understanding. And as in the standard rationality paradigm, I assume that the partial understanding of players as parameterized by their cognitive type is correct. The heart of the project is to show how these approaches can be used to shed new light on major subfields of economic theory such as mechanism design, the theory of reputation, the theory of incomplete contracts and the theory of speculative markets. I also wish to test experimentally the solution concepts so as to check their empirical validity.

678 370 €

Start date: 2009-01-01, End date: 2013-12-31

The molecular cross talks occuring at the interface between the intestinal epithelium and bacterial flora will be studied at two levels : (i) how commensals and pathogens affect innate immune signalling, thereby leading to tolerance of the resident microbiota, and inflammatory rejection of the pathogens. The theme of commensals and pathogens regulating this innate response, particularly how they respectively strengthen or weaken the network of humoral and cellular epithelial defense systems will be central here. (ii) How, in molecular and cellular terms, bacteria affect epithelial renewal. The gut of a germ-free mouse and of a conventional mouse show dramatic differences marked by global immaturity and slow epithelial renewal in absence of flora. In front of pathogens, the actual role plaid in the disease in altering the kinetics of epthelial repair is unknown. The aim of this project is to study how commensals and pathogens affect intestinal epithelial renewal, particularly the key steps of the whole developmental process such as lineages decisions, entry in cycle and proliferation, migration and final differentiation, decision to engage in cell death. In order to address these fundamental questions, we will study a commensal microorganism : Lactobacillus casei, and a pathogenic microorganism : Shigella flexneri as model organism, and will develop several novel systems such as reverse genetics of Lactobacilli, development of intestinal crypt models in vitro to study bacterial interactions, and development of a mouse model showing susceptibility to human-specific enteroinvasive pathogens. This project aims at interfacing microbiology, cell biology, and development biology around the concept of microbes manipulating intestinal epithelial homeostaesis. It also includes a strong component of therapeutic development aimed at identifying novel anti-infectious strategies and options to speed up epithelial restitution upon infectious-inflammatory damages.

2 356 350 €

Start date: 2009-02-01, End date: 2014-03-31

This is a proposal to define a fundamentally new and potentially dominant pathway of airway inflammation involving the p53 homolog p73 acting through regulators of cytokine mRNA stability. We anticipate that the studies described herein will contribute to our understanding of acute and chronic airway diseases and the development of novel therapies to combat them. The proposal is divided into four parts: 1. Establish a Role for p73 in the Innate Immune Response in the Upper Airways Our genetic models for loss of p73 function reveal the unexpected finding that ciliated airway epithelia play a major and perhaps dominant role in airway inflammation. We will exploit genetic and cellular models to establish the broader significance of these cells and of p73 in regulating the innate immune response and how they contribute to human disease. 2. Define the Signaling Pathways of the Innate Immune Response in Airway Epithelia We will use mass spectrometry, shRNA technology, and small molecule inhibitors to dissect these pathways linking p73 to airway inflammation and develop chemical screens as a basis of therapeutic intervention. 3. Determine the Genetic Targets of p73 that Control Airway Inflammation Our preliminary work has identified key regulators of mRNA stability downstream of p73, and has implicated them in the destabilization of inflammatory ytokine mRNAs. These observations suggest a novel mechanism for the control of airway inflammation involving mRNA stability. 4. Mouse Models for Dcp1² Loss-of-Function The identification of Dcp1² as the strongest target of p73 offers a new and fundamental approach to the control of airway inflammation. Genetic models in mice will provide new insights into the role of mRNA stability for airway inflammation and novel models of human airway disease.

2 470 400 €

Start date: 2009-07-01, End date: 2010-12-31

The aim of this research proposal is to provide a unified framework to evaluate and to manage collective long-term risks, with applications to environmental risks (climate change, genetically modified organisms, nuclear wastes, non-renewable resources, biodiversity, &). What should we be willing to give up to reduce these risks? What is the best timing for action? How should the risk evaluation be adapted to the absence of objective probabilities, the conflicts between and biases in individual beliefs, the heterogeneity of individual preferences towards these risks, the ability to predict future impacts, the limited capability to share risk efficiently, or the changing expectations about long-term economic growth and about the scarcity of environmental resources? To examine these questions, we will combine various approaches from modern decision theory, the theory of finance, environmental economics and behavioural economics. This research is also aimed at helping collective decision making by improving the standard tools of benefit-cost analysis for the specificities of long-term risks: discounting of far distant effects, risk premium for fat tails, ambiguity premium, aggregation rules for heterogeneous beliefs and preferences, and option values. We will translate general concepts as sustainable development , corporate social responsibility and precautionary principle into efficient guidelines for collective decision making.

1 400 000 €

Start date: 2009-01-01, End date: 2014-12-31

We propose innovative approaches to electronic quantum noise going from very fundamental topics addressing the quantum statistics of few electrons transferred through conductors to direct applications with the realization of new types of versatile broadband photon detectors based on photon-assisted shot noise. We will develop electron counting tools which will not only allow to full characterization of electron statistics but also open the way to new quantum interference experiments involving few electrons or fractional charge carriers and will question our understanding of quantum statistics. Generation of few electron bunches will be obtained by the yet never done technique of short voltage pulses whose duration is limited to few action quanta, one quantum for one electron. Detection of electron bunches will be done by an unprecedented technique of cut and probe where carriers are suddenly isolated in the circuit for further sensitive charge detection. Using highly ballistic electron nanostructures such as Graphene, III-V semiconductors with light carriers, Carbone Nanotubes or simply tunnel barriers, we will bring mesoscopic quantum noise effects to higher temperature, energy and frequency range, and thus closer to applications. Inspired by late R. Landauer s saying: the noise IS the signal we will develop totally new detectors based on the universal effect of photon-assisted electron shot noise. These versatile broadband detectors will be used either for on-chip noise detection or for photon radiation detection, possibly including imaging. They will operate above liquid Helium temperature and at THz frequencies although projected operation includes room temperature and far-infrared range as no fundamental limitation is expected. The complete program, balanced between very fundamental quantum issues and applications of quantum effects, will open routes for new quantum investigations and offer to a broad community new applications of mesoscopic effects.

1 999 843 €

Start date: 2009-02-01, End date: 2015-01-31

Host-pathogen interactions have recently received much attention. Yet, a more comprehensive understanding of these interplays should provide fundamental advances in biology and help generating new therapeutics. The intracellular bacterium Listeria monocytogenes has emerged as an exceptional model organism to address key questions in biology such as actin-based motility, phagocytosis and post-transcriptional regulation. We will exploit our deep knowledge of Listeria and use this bacterium as a model to explore new landmarks in biology. In that aim, we will analyze several aspects of the infectious process, in a spatio-temporal fashion, at the bacteria, cell, tissue and host levels. Specifically, we will 1) search and analyze the function of new non-coding RNAs involved in virulence, and of new RNA-mediated regulations; 2) investigate new facets of bacterial entry and cell-to-cell spread in particular the role of uncharacterized cytoskeletal components, septins; 3) address the role of mitochondria and their dynamics in infection; 4) systematically analyze post-translational modifications during infection, starting with SUMOylation, a reversible modification and proteolysis, an irreversible one; 5) investigate chromatin remodeling upon infection; 6) characterize new virulence factors identified by their interaction with known signaling components or cellular sensors, by post genomics or by their effect on cellular responses analyzed herein ; 7) investigate further the intestinal phase of Listeria infection by analyzing in the germ-free transgenic mouse that we generated, the impact of commensals on Listeria (growth and transcription including non-coding RNAs) and on the intestinal tissue (histology and transcription of genes and microRNAs). Our main goal is to improve significantly our understanding of bacterial infections, by discovering important new concepts in microbiology, cell biology and infection biology thereby opening new avenues for further research.

1 800 000 €

Start date: 2009-06-01, End date: 2015-05-31

Consubstantial to the founding project of social sciences, moral issues have been eclipsed for a long time in sociological and anthropological research. Without neglecting recent efforts of social scientists to readdress them, my intention is to take up this repressed ambition by laying the foundations of a critical moral anthropology. The crucial importance of morals in everyday life as well as in global crisis, in the evaluation of actions as well as in the justification of policies, in the relations with others as well as in the construction of social identities makes this ambition a reasonable necessity. Empirical validation will be done through a comparative ethnography of moral economies around two groups: immigrants in juridical precariousness; adolescents from underprivileged areas. Our study will concern their interactions with regulation structures police and justice, social work and mental health. It will enlighten the concepts of moral work and stakes, of moral categories and evaluation, of moral communities and boundaries. Fieldwork will be mainly conducted in the banlieues of Paris. For the immigrants, we will study how situations and claims are evaluated at the border to enter the territory (Waiting Zone for Foreigners of Roissy) or in case of appeal for refugees (National Court for Asylum); we will also analyze processes of sanction for their illegal situation (Retention Center of Coquelles) or for offences (Prisons of La Santé, Fresnes and Val d Oise). For the adolescents, we will focus on the ordinary setting of institutions in charge of these publics (Val d Oise), but also on two innovative responses based on mental health (Network of Yvelines Sud and House for Adolescents of Val d Oise East). Based mainly on anthropology and sociology, the project also involves political science, philosophy, psychology and psychiatry. The research team includes the PI, 5 post-docs, 5 PhD students and two part-time researchers, all from IRIS.

1 286 400 €

Start date: 2009-07-01, End date: 2013-06-30

The essence of the proposal is the fabrication of multiple nano containers which exhibit double and triple stimuli response and site recognition. Specifically, the containers will be grafted by Leuprolide (LP) for prostate cancer recognition. Multiple containers will be filled by two drugs (e.g. LP and DOX) in different compartments not interacting with each other chemically (cocktail of drugs, e.g. Container1 Leuprolide (LP) and Container2 Doxorubicin (DOX)). The release can be excited by internal or external stimuli response. The internal stimuli response of our nanocontainers will require simultaneous recognition of pH, redox and/or T of the tumour. The external induction will be caused by RF excitation (hyperthermia). The nanocontainers will identify the tumour first by the agonist (LP). After trapping the container at the tumour, they will be activated by the double and triple internal excitation. This way, we achieve extremely local chemotherapy of the diseased site and the healthy organs will be untouched. Our smart nanocontainers will be tuned for prostate cancer, but our system will be evaluated for other cases such as breast cancer and thrombosis. The containers will be modified (phase transition, volume change, degradation, etc.) and deliver the drug only and if only the two sensors give positive response. The containers can be excited by external induction (Radio Frequency (hyperthermia) RF or laser light). This revolutionary strategy is necessary because the externally induced delivery methods have the disadvantage that the radiofrequency fields, the magnetic fields and the laser lights are not local but they extend over large space, larger than the size of the tumour. One cannot focus from outside the laser beam directly to the tumour only may be due to lack of imaging facilities. Our technology will prevent the release of drugs in sites where the local values correspond to the healthy tissue.

2 000 000 €

Start date: 2009-02-01, End date: 2014-01-31

Ageing is associated with marked decrease of neuronal function and increased susceptibility to neurodegeneration, in organisms as diverse as the lowly worm Caenorhabditis elegans and humans. Although, age-related deterioration of the nervous system is a universal phenomenon, its cellular and molecular underpinnings remain obscure. What mechanisms are responsible for the detrimental effects of ageing on neuronal function? The aim of the proposed research programme is to address this fundamental problem. We will implement an interdisciplinary approach, combining the power of C. elegans, a highly malleable genetic model which offers a precisely defined nervous system, with state-of-the-art microfluidics and optical imaging technologies, to manipulate and monitor neuronal activity during ageing, in vivo. Our objectives are four-fold. First, develop a microfluidics platform for high-throughput manipulation and imaging of specific neurons in individual animals, in vivo. Second, use the platform to monitor neuronal function during ageing in isogenic populations of wild type animals, long-lived mutants and animals under caloric restriction, a condition known to extend lifespan from yeast to primates. Third, examine how ageing modulates susceptibility to neuronal damage in nematode models of human neurodegenerative disorders. Fourth, conduct both forward and reverse genetic screens for modifiers of resistance to ageing-inflicted neuronal function decline. We will seek to identify and thoroughly characterize genes and molecular pathways involved in neuron deterioration during ageing. Ultimately, we will investigate the functional conservation of key isolated factors in more complex ageing models such as Drosophila and the mouse. Together, these studies will lead to an unprecedented understanding of age-related breakdown of neuronal function and will provide critical insights with broad relevance to human health and quality of life.

2 376 000 €

Start date: 2009-05-01, End date: 2015-04-30

DNA replication origins remain poorly defined in metazoans, in contrast to bacteria or S. cerevisiae. We believe that, in eukaryotes, a differential encoding of chromosomes by DNA replication origins is instrumental for the acquisition of cell identity during development. We wish to decipher this encoding, to determine whether it is linked to gene expression, and identify the mechanisms used to build a replication origin. First, we will unravel the origins code in mouse undifferentiated pluripotent cells with a genome-wide approach and correlate the replication origins' map with other chromosomal genetic or epigenetic features. The origins code will be deciphered also in the same cells when engaged into a specific (neural) differentiation. We predict that this differential mapping will identify constitutive and regulated origins, the latter specific to gene domains expressed in differentiation and providing cell identity. In the second axis of this project, we will identify proteins that constitute a replication origin. We will exploit two novel screening procedures developed in our laboratory. The "chromosome-trap" assay uses DNA beads to collect factors assembling at replication origins, using Xenopus cell-free systems. The "Replication foci capture" method allows the isolation of replication origins at their in-situ chromosomal location. Key objective 1: to unravel DNA replication origins' code in pluripotent embryonic stem cells. Key objective 2: to identify a link between replication origins and cell identity . Key objective 3: to investigate whether replication origins are responsible for the spatio-temporal organization and cell identity regulation by Homeobox domains. Key objective 4: to perform a functional analysis of replication origins by SiRNA silencing of differentially expressed gene domains or specific KO of DNA replication origins. Key objective 5: to identify new factors which assemble replication origins by two novel screening procedures.

2 000 000 €

Start date: 2009-02-01, End date: 2014-01-31

Integrative phagosomal biology: antigen presentation and developmental programs in dendritic cells Dendritic cells phagocytose incoming pathogens and dead cells in peripheral tissues, and then migrate to the draining lymph nodes where they deliver to lymphocytes all the information required for the initiation of adaptive immune responses. This information relates to the nature of the pathogen, which is sensed, both directly through pattern recognition receptors (including Toll-like receptors, TLRs), and indirectly through different receptors for cytokines and stress factors. This information also concerns the structure of the antigens, which will be presented to T lymphocytes in the form of proteolytic peptides loaded on MHC molecules. Phagosomes play a critical role in the processing of antigens for presentation to both MHC class II-restricted CD4+ T cells, and to MHC class I-restricted CD8+ T cells (a process called cross presentation). Importantly, antigen processing and presentation to T cells is influenced by the environment of the dendritic cells and by the type of TLR-ligands engaged. The present project aims to identify the molecular basis for the regulation of phagosomal functions (including oxidation, pH control and degradation) and antigen processing during the different developmental programs of DCs. Our main specific aims are: 1) to analyse the regulation of the phagosomal function during dendritic cell maturation, 2) to identify novel molecular players and pathways in antigen cross presentation using shRNA- based screens, and 3) to image dynamically phagocytic dendritic cell functions, in vitro and in vivo. This project will provide an integrated vision of the phagosomal function of dendritic cells and of its regulation during dendritic cell maturation. It will unravel novel molecular players and pathways involved in the control of the phagocytic function in general, and will contribute to understanding the molecular basis of immune recognition.

2 214 702 €

Start date: 2009-07-01, End date: 2014-06-30

The aim of the PopPhyl project is to characterize the population genetic environment of many representative plant and animal species, in order to elucidate which biological and ecological factors determine molecular evolutionary processes - we want to know why genomes evolve the way they evolve. We will establish predictions about the influence of ecological (population size, varying environment) and genetical (mating systems, life cycle, mutation rate) variables on comparative genomic patterns thanks to improved molecular evolutionary theory relying on Fisher's geometric model. Predictions will be checked empirically by collecting extensive data sets of within-species and between-species genomic diversity in a large number of well-chosen taxa, with monitored life history traits. Massive gene sequences will be obtained from the extraction and analysis of abundant mRNA's, ensuring comparability between even distant taxa. These data will allow us to assess, and compare across species, the population genetic parameters relevant to molecular evolution: effective population size, mutation rate, strength of positive and negative selection. The main focus of the project is on the influence of population size, mating systems and life-span on molecular evolutionary rates. Are abundant species genetically more diverse? Do they adapt more efficiently? Is self-fertilization the evolutionary dead-end it is said to be? Why are fast-evolving proteomes fast: higher mutation rate, or prominent adaptive evolution ? PopPhyl is an ambitious, long-term multi-disciplinary project lying at the boundary of phylogenetics and population genetics, and requiring intensive theoretical and bioinformatic developments. We want to explore a new dimension of evolutionary biology by making population genetics comparative, and by injecting species ecology into genomic analyses.

2 000 000 €

Start date: 2009-07-01, End date: 2013-12-31

This project proposes to carry out the first large scale investigation into the typology of Sinitic or Chinese languages, broadening its horizons beyond Standard Mandarin to consider the major parameters in the grammatical makeup of this language taxon with respect to the neighbouring language families of East and Southeast Asia. The principal objective is to examine and seek explanations for the apparent hybrid typology of Sinitic languages which reveal a perplexing mixture of head-final and head-initial features and consequently pose several striking counterexamples to classic Greenbergian word order correlations. The theoretical issue involved is to question accounts which purely rely upon areal diffusion to explain this, without considering language-internal development, in particular syntactic change, as an interacting component. Complicating research in this field is the fact that Standard Mandarin is generally the main, if not, only point of reference for Sinitic languages in typological studies in the West, while until recently it persisted as the primary object of analysis in Chinese linguistics in general. Thus, a macroscopic survey of the ten branches of Sinitic is first proposed to describe their fundamental syntactic properties and word order correlations in detail. Second, the project sets out to challenge and refine the hypothesis of a North-South typological dichotomy for Sinitic languages based on areal principles and advocated by Hashimoto and Norman. To this purpose, the research plan also includes a comprehensive analysis of the grammar of Waxiang, a language spoken in remote northwest Hunan province and chosen to represent the transitional zone of Chinese languages in central China . Significantly, this language shows characteristics of an intermediate nature between northern and southern Sinitic , expected to assist in elucidating the issue of hybrid typological features.

1 863 528 €

Start date: 2009-01-01, End date: 2013-06-30

Understanding how the genetic information of a cell is retrieved but also protected from insults, is a major challenge facing modern molecular biology. Indeed, one of the most important developments in human genetics over the last decade, has been the realization that diseases such as cancer but also ageing stem from some dis-regulation in the expression and preservation of the genetic information. TFIIH is a multiprotein complex that is essential in transcription and DNA repair. Mutations in some of its subunits are responsible of a UV sensitivity phenotype in yeast and drosophila. In human, this results in the rare DNA repair deficient genetic disorder, xeroderma pigmentosum (XP), which is characterized by photosensitivity and an increased risk of skin cancers. Two further disorders involving mutation in TFIIH subunits, Cockayne syndrome (CS) and trichothiodystrophy (TTD) are also defective in repair of UV damage, but present quite different clinical features such as brittle hair, neurological and developmental retardation, middles sun sensitivity and no susceptibility to solar carcinogenesis. The clinical complexity of these syndromes cannot be explained solely by deficiencies in DNA repair and emerging evidences indicate that it may also result from a dys-regulation of the transcriptional program under the control of hormones. The goal of this proposal is to investigate the DNA repair/transcription disorders involving mutations in TFIIH. This research will not only assists afflicted XP, CS, TTD and normal individuals in prevention and ultimately cures of hormonal dependent diseases and cancer (the clinical point of view), but more generally will provide an improved understanding of the mechanisms that regulate the expression of protein coding genes and the maintenance of genome integrity (the fundamental research point of view).

1 997 000 €

Start date: 2009-01-01, End date: 2013-12-31