A growing interest has focused on intrinsically disordered proteins (IDPs) the last few years. It is now recognized that IDPs constitute a newly recognized class of protein, which defy the structure–function paradigm as they fulfill essential biological functions while lacking well-defined secondary and tertiary structures. Such proteins are in fact common in living organisms and occupy a unique niche in which function is intimately linked with structural disorder. Protein disorder is a general phenomenon and the structural and functional exploration of this protein class is one of the most challenging and imperative task various branches of protein science face in the post-genomic era. A crucial property of intrinsically disordered proteins and regions that could contribute to their function in signaling networks is binding diversity; i.e., their ability to partner with many other proteins and other ligands, thanks to their structural plasticity. Many IDP mediate interactions through a disorder-to-order transition upon binding to their biological targets, a process termed induced folding. Different analyses of sequence databases have shown that they were very abundant in eukarya and mostly implicated in cell signaling and cell cycle. In particular, it appears that a considerable amount of proteins involved in cancers contain large disordered regions. The importance of intrinsic disorder in cancer-related proteins opens therefore new perspectives in drug discovery process from the identification of novel targets to the development of lead compounds with desired properties. We therefore develop a new project on IDPs, specifically involved in Leukemia with the aim of developing new therapeutic strategies based on structure-based drug design. Leukemias are characterized by the uncontrolled proliferation of white blood cells or their precursors. It represents about 10% of all cancers, while leukemia incidence rates increase slowly. Despite recent advances in the treatment of leukemia, most current chemotherapies lead to resistance after a relapse, and stem cell transplant can cure leukemias, which can cause numerous side effects and poses many risks of fatal complications. There is therefore a crucial need for new strategies to be developed in the treatment of Leukemias Among the numerous predicted human IDPs involved in cancer, the fusion protein BCR-ABL, resulting from the chromosomal translocation t(9;22) is responsible of the Chronic Myelogenous Leukemia (CML). Altered expression of Notch Intracellular domain (NICD) is also found in lymphocytic leukemias. These proteins contain large disordered regions that act as hubs, interacting with many different partners in the cell. While much information has been gathered on their folded domains, the structural mechanisms of the interactions involving their disordered regions have never been studied so far. The project will be structured in 3 main steps : (i) a structural characterization of the isolated intrinsically disordered domains of BCR, ABL and NICD (ii) a thermodynamic analysis of the interactions of these proteins with cellular partners (iii) a thorough structural characterization of the most relevant interactions analyzed in the previous step. Structural disorder will be assessed using an ensemble of experimental techniques that will allow to describe thoroughly the structural properties of these proteins In particular, all these experiments will aim at finding the presence of putative residual structures that could initiate an induced folding upon binding to a partner. Circular dichroism, dynamic light scattering and small angle scattering will assess the global structural properties of the isolated disordered domains and of the full length proteins in solution, and complexed to their partner. On the other hand, NMR will investigate the presence of residual structure and structural determinants of the interactions at the residue level. All this work will allow a precise and complete characterization of the structural determinants of these protein interactions, essential in the cell signaling and regulation processes of these proteins in Leukemia This work will first bring valuable information on the structural properties of intrinsically disordered proteins and on the protein interactions that such proteins can established. Results obtained from experimental studies will therefore be complementary to the predicting computational approaches and improve the current knowledge on the function and mode of action of these peculiar proteins. Then, the understanding of this highly complex systems, and the role of the disordered regions of BCR-ABL and Notch in cell signaling and regulation processes will be improved, and will lay the bases for structure-based drug design and new therapeutic strategies.

Bacteria of the genus Brucella are the causative agents of brucellosis, a worldwide zoonosis that affects a variety of mammals including humans. Human brucellosis is a debilitating chronic disease with an eventual fatal outcome, which results from the systemic spread of Brucella to various organs. Essential to a successful infection is the ability of Brucella to invade, survive and replicate inside both phagocytic and non phagocytic cells. However, the underlying mechanisms of these events are still unclear. Brucella infection also occurs due to the immunosuppressive function of its virulence factors. Our aim is to characterize the effect of Brucella infection on the most potent professional antigen presenting cells (APCs) known, the dendritic cells (DCs). Using in vitro and in vivo approaches, we will characterize the impact of Brucella LPS and its effectors on mouse DC function both at the cellular and immunological level. Dendritic cells (DCs) were initially identified for their unique ability to present antigens and prime naïve CD4+ and CD8+ T lymphocytes. We have shown that DCs are efficiently infected by Brucella both in vitro and in vivo. However little is known on the role of DCs during Brucella infection and pathogenesis. What is the role of Brucella Btp effectors in the activation/migration step of Brucella-infected dendritic cells? What is the outcome of the immune response induced by these infected cells? It is crucial to characterize the processing and presentation of Brucella antigens by DCs to understand the bacterial evasion strategies. DCs constitute a bridge between the innate and adaptive immunity as they are activated upon encounter with pathogens through innate receptors and respond by triggering adaptive T cell responses. We have shown that Brucella through different secreted effectors control the process of DC activation and inhibits different functions such as cytokine production and antigen presentation, thereby possibly creating anergizing conditions for T cells stimulation. The interaction of Brucella with DCs is therefore likely to affect the outcome of infection and the development or not of host protective immunity. The interaction of live Brucella with DC and the effects of its virulence factors on DC maturation and T cell activation will be further investigated. Mouse DCs will be infected with different mutants of Brucella and the impact on their function will be studied by immunogical and cell biological methods. In particular the importance of two effectors Btp1 and Btp2 will be evaluated in vitro. We will focus on cytokine production and antigen specific responses both trigered by MHC I and MHC 2 in DCs. In vivo studies will be performed using mutants bacteria and various transgenic mouse strains. to monitor the Brucella induced immune responses and define the impact of DC infection on these responses. The competences of the two proposing teams in Brucella-host interactions (J-P Gorvel) and in the cell biology of dendritic cells (P. Pierre) should synergize to bring new insights on the importance of Dendritic cells for Brucella infection. Our research should define the function of several Brucella effectors and their importance to establish a successful infection. in addition the manipulation of the immune system by Brucella should also yield precious information on the function of dendritic cells as master regulators of the immune system and how these cells control the extent of the immune response according to the environmental context. Finally we hope to develop strategies to counteract the immunosupressive activity of Brucella, in order to reduce the chronicity of the disease in animal models.

Every area of modern mathematics has a fundamental classification problem, to which the whole research in that area is directly on indirectly related. The fundamental problem of complex geometry is the classification of compact complex manifolds. Whereas in the classification of projective algebraic complex manifolds (and more generally of Kählerian manifolds) remarkable progress has been made in arbitrary dimension, the non-Kählerian manifolds still pose huge difficulties even in dimension 2. Our project “New Methods in Non-Kählerian Geometry” is mainly dedicated to this classification problem of complex manifolds in the non-Kählerian framework, and related problems. More specifically, the research topics to be treated during the duration of the project will be: - Classification of non-Kählerian surfaces, - Local index theorems and Grothendieck-Riemann-Roch type theorems in non-Kählerian geometry, - Special metrics on non-Kählerian manifolds, - Foliations and group-actions on complex manifolds We explain briefly the importance of these topics and the relations between them. The methods developed for the algebraic and Kählerian case are not directly applicable to the non-Kählerian framework. On the other hand, thanks to the conjugated efforts of several experts (and in particular of some participants in this project), important results concerning the classification of non-Kählerian surfaces have recently been obtained. These results revived the interest in this theory within the mathematical community and revived the hopes to have soon a complete classification. In order to extend these new methods to the general case (class VII surfaces with arbitrary second Betti number) we noticed that one needs a very fine version of the famous Grothendieck-Riemann-Roch theorem for holomorphic families, which is not known at this moment. More precisely, one needs a method to compute the Chern character of the total direct image in the Bott-Chern cohomology (or in the Deligne cohomology of the base). The problem appears to be very difficult, even for the best experts in the field, so we included the second topic in our project (which is obviously important independently of the the other three). One of the hottest topics in modern complex geometry is the theory of “special metrics”. The idea is very natural: endow every compact complex manifold with a Hermitian metric which is optimal (for instance minimizes a certain functional). This idea (which relates complex geometry to global analysis and differential geometry) has been intensively developed in the algebraic and the Kählerian case. For instance, the theorems of Aubin-Yau concerning the existence of Kähler-Einstein metrics can be regarded as the first concretization of this program. But recently new spectacular results (obtained for instance by Donaldson, Tian and many others) showed that this idea can be applied to a much broader class of Kählerian manifolds, using he appropriate class of metrics (for instance extremal, or constant scalar curvature Kählerian metrics). Our team will mainly concentrate on existence and classification of bihermitian and locally conformally Kähler metrics, which are known to exist on certain non-Kählerian surfaces. We will also consider nearly Kähler structures. An important problem related to the classification of complex surfaces (in particular non-Kählerian surfaces) is the following: which complex surfaces admit holomorphic foliations? For the surfaces for which the answer is positive, one can further ask for the classification of all possible holomorphic foliations. For non-Kählerian surfaces these questions are particularly important, because (as shown by Dlousky-Oeljeklaus-Toma) surfaces which admit certain types of holomorphic foliations can be easily classified.

Chloroplasts are essential organelles that are the site of photosynthesis in green plants. By capturing and converting sun light photosynthesis is the primary source of chemical energy for the whole biosphere. Chloroplasts were formed when a eukaryotic cell swallowed an ancient cyanobacterium. Today bacteria-like processes including photosynthesis, transcription and translation continue within the chloroplast, with the addition of new eukaryotic processes such as hormone and starch metabolism. Chloroplasts are now at the heart of plant energy metabolism and are delicate sensors of the outside environment and the specific nutrient requirements of the plant. Here we propose to find out how chloroplasts sense environmental change and how they then signal to mediate chloroplast and plant-wide acclimation. Progress in these areas will open up new horizons in plant biology, and will be crucial for improving plants to face the challenges of a changing climate (by development of drought and salt tolerant crops and plants for carbon dioxide sequestration) and uncertain energy supplies (by development of plant-based alternatives to fossil fuels and petrochemicals).