ERC FUNDED PROJECTS

This project will focus on the use of nanoporous metal organic frameworks (Fe, Zn, Ti) for bioapplications. These systems are exciting porous solids, built up from inorganic clusters and polycarboxylates. This results in open-framework solids with different pore shapes and dimensions, and applications such as catalysis, separation and storage of gases. I have recently initiated the synthesis of new trivalent transition metal carboxylates. Among them, the metal carboxylates MIL-100 and MIL-101 (MIL: Materials of Institut Lavoisier) are spectacular solids with giant pores (25-34 Å), accessible metal sites and huge surface areas (3100-5900 m2.g-1). Recently, it was shown that these solids could be used for drug delivery with a loading of 1.4 g of Ibuprofen per gram of MIL-101 solid and a total release in six days. This project will concentrate on the implication of MOFs for drug release and other bioapplications. Whereas research on drug delivery is currently focused either on the use of bio-compatible polymers or mesoporous materials, our method will combine advantages of both routes including a high loading and a slow release of therapeutic molecules. A second application will use solids with accessible metal sites to coordinate NO for its controlled delivery. This would provide exogenous NO for prophylactic and therapeutic processes, anti-thrombogenic medical devices, improved dressings for wounds and ulcers, and the treatment of fungal and bacterial infections. Finally, other applications will be envisaged such as the purification of physiological fluids. The project, which will consist of a systematic study of the relation between these properties and both the composition and structure of the hybrid solids, will be assisted by a strong modelling effort including top of the art computational methods (QSAR and QSPKR). This highly impact project will be realised by assembling experienced researchers in multidisplinary areas including materials science, biology and modelling. It will involve P. Horcajada (Institut Lavoisier), whose background in pharmaceutical science will fit with my experience in inorganic chemistry and G. Maurin (Institut Gerhardt, Montpellier) expert in computational chemistry.

1 250 000 €

Start date: 2008-06-01, End date: 2013-05-31

Chemical samples often come as solution mixtures. While advanced analytical methods exist for samples at equilibrium, the information on components and their interactions that may be accessed for the frequent and important case of out-of-equilibrium mixtures is much more limited. The DINAMIX project will tackle this challenge and provide detailed, molecular-level information on out-of-equilibrium mixtures. The proposed concept relies on diffusion nuclear magnetic resonance (NMR) spectroscopy, a powerful method that separates the spectra of mixtures’ components and identifies interactions, in correlation with structural insight provided by NMR observables. While classic experiments require several minutes, spatial encoding (SPEN) in principle makes it possible to acquire data orders of magnitude faster, in less than a second. The PI has recently demonstrated that SPEN diffusion NMR is a general concept, with the potential to provide real-time information on out-of-equilibrium mixtures. These include a vast range of systems undergoing chemical change, as well as the important class of “hyperpolarised” solution mixtures generated by dissolution dynamic nuclear polarisation (D-DNP). D-DNP indeed provides dramatic NMR sensitivity enhancements of up to 4 orders of magnitude, which however last only for a short time in solution. In the DINAMIX project, we will develop i/ novel robust and accurate real-time diffusion NMR methods, ii/ advanced algorithms for data processing and analysis, iii/ protocols for sensitive component identification. We will exploit the resulting methodology for mechanistic investigations into catalytic organic and enzymatic reactions. The real-time diffusion NMR analysis of systems that are out-of-chemical equilibrium, far-from-spin-equilibrium or both will provide transformative insight on mixtures, with applications in chemical synthesis, supramolecular and polymer science, structural biology, and microstructural studies in materials and in vivo.

1 499 307 €

Start date: 2019-02-01, End date: 2024-01-31

Paramyxoviruses, including, measles and a number of dangerous human pathogens, are negative strand RNA viruses that express their own machinery for transcription and replication. Different interactions between the nucleoprotein (N) and the phosphoprotein (P) are essential for chaperoning and assembly of N on newly synthesized RNA genomes to form nucleocapsids (NCs), as well as for initiating replication and transcription. Both N and tetrameric P exhibit extensive conformational disorder, with very long, unfolded regions that host important post-translational modification sites as well as regulatory interactions with host and viral partners. The presence of this level of disorder, in viruses whose genetic information is normally so parsimoniously exploited, remains unexplained. The elaboration of time-resolved, atomic resolution descriptions of the interaction trajectories of these highly disordered N:P complexes is extremely challenging, requiring the development of adapted methodologies that can account for their intrinsic flexibility. The role of N and P has been rendered yet more enigmatic following our recent observation that when mixed in solution they form liquid-like droplets. Such membraneless organelles are revolutionizing our understanding of cellular chemical biology, although their physical basis is poorly understood. Our aim is to describe these important complexes at atomic resolution, in particular to understand the role of the extensive conformational dynamics of N and P in the replication cycle. Our recent success in engineering soluble N:P complexes from measles that assemble into NCs, combined with ongoing development of NMR-based methods to investigate the structure, dynamics and interaction kinetics of large, intrinsically disordered proteins, fluorescence spectroscopy, cryoEM, SAXS, crystallography and molecular simulation, will provide the essential tools to investigate the functional mechanisms of these previously inaccessible complexes.

2 499 150 €

Start date: 2019-11-01, End date: 2024-10-31

The idea has emerged that compartmentation of brain lactate, i.e. its distribution between different cell types and the extracellular space, plays a critical role in neurotransmission and brain plasticity. Dysregulations of lactate metabolism have also been reported in neurodegenerative diseases such as Alzheimer's disease. However, these notions remain challenged, and even fundamental mechanisms such as the astrocyte-to-neuron lactate shuttle, whereby astrocytes are supposed to export lactate to neurons to sustain neuronal energy needs, are still fiercely debated. This is largely due the lack of tools to evaluate cell-specific compartmentation of lactate in the living brain, in particular in Humans. In this project, we will develop new nuclear magnetic resonance spectroscopy techniques to non-invasively measure lactate diffusion, including in cortical regions. We will then take advantage of the unique ability of these methods to differentiate between metabolites diffusing in different environments, based on diffusion properties imposed by the microstructure, to quantify lactate in the extracellular space and, most importantly, in neurons and astrocytes. After validation in rodent models, these methods will be transposed on a clinical MRI system at ultra-high magnetic field, to gain unprecedented access to lactate compartmentation in the Human brain and its modifications during brain activity, plasticity, and in Alzheimer's disease. This will open a new research field for magnetic resonance spectroscopy in vivo.

1 999 868 €

Start date: 2019-05-01, End date: 2024-04-30