Considering the scientific evidence supporting that regular physical exercise enhances cognitive performance across the lifespan, the World Organisation of Health advocates regular physical activity to prevent neurodegenerative diseases and early-onset dementia. Among the several neurophysiological mechanisms involved/evoked to explain cognitive enhancement, the mechanism of neurovascular coupling (NVC), seems to be of paramount significance. This mechanism is especially crucial, as a decrease in NVC can account for the age-related cognitive decline and may also contribute to the onset of neurodegenerative diseases. Nonetheless, several cross-sectional studies have observed that individuals with higher levels of physical fitness, thanks to regular physical activity, exhibit greater NVC in the prefrontal cortex, associated with better executive cognitive performance. However, a comprehensive understanding of the cellular and molecular mechanisms associated with NVC in humans, the use of animal models is required. Longtime considered as a metabolic waste product, lactate now could play a key role in the interplay between physical exercise and cognitive functioning, primarily through its functions as a cellular messenger and substrate. The main objective of this research project, adopting translational and multidisciplinary approaches, is to determine the specific role of endogenous lactate resulting from physical exercise in the neurovascular coupling associated with cognitive improvements. To reach this objective, this multidisciplinary project will be carried out thanks to 4 work packages. Two of them will be devoted to animal studies and the two remainders to human studies. Investigating the underlying neurophysiological mechanisms between physical exercise and cognitive performance has a direct societal impact: To prescribe the appropriate type of physical exercise to promote cognitive health.

The aim of this work is to develop a new theranostic approach based on intratracheal inhalation of multimodal contrast agent for lung pathologies (in these cases lung tumours and the vascular component of airway remodelling in asthma) as compared to the commonly used intravenous administration. The contrast agent developed for this application is a multimodal UltraSmall Rigid Particle (USRP) that can be followed by different complementary imaging techniques (Magnetic Resonance Imaging, fluorescence imaging, scintigraphy, X-Ray tomography). The combination of the advantages of these different modalities will permit a complete imaging characterization of healthy and diseased regions in lungs with the highest resolution and sensitivity currently available but, in addition, this will also pave the way toward image-guided and activated therapy. The intrapulmonary delivery of the contrast agents is expected to give access to new mechanisms of contrast agent uptake and targeting of diseased areas in the lungs. The USRP multimodal contrast agent was recently synthesised in the LPCML and it has proved its effectiveness in oncology for multimodal imaging and therapy. This ultrasmall nanoparticle (size inferior to 5 nm) obtained via an original top down process is composed of a polysiloxane matrix and chelating species (like commercial agents DTPA and DOTA) at the surface of the particles. The presence of anchoring chemical functions at the surface of the particle also permits the further functionalization by targeting molecules. Preliminary tests performed in collaboration with the team of Y. Cremillieux (CRCT, Université Bordeaux Segalen) have shown a clear enhancement of the contrast of MRI images in the lungs after nanoparticles injection via the airway with homogenous distribution. This has been achieved thanks to the use of new MRI sequences developed by CRCT. In parallel to these experiments, fluorescence imaging combined with Computed X-ray Tomography (CT) has been performed by IAB in tight collaboration with Nano-H S.A.S. The same type of distribution was observed but complementary quantitative data has been obtained like more sensitive quantification, simplicity of quantification and easy access to functional imaging. Based on these first results, the aim of this project is to validate the interest and properties of these USRP as well as targeted USRP-derivatives for the diagnostic of lung diseases using intratracheal administration. For each validation step, the inhalation route will be compared to the “standard” intravenous injection route. Two types of lungs diseases will be essentially studied in this proposal: asthma and lung cancer. The addition of cyclic RGD peptide (recognized to target the integrins avß3) on the nanoparticles will permit an accumulation of the nanoprobes in the lung tumours as well as in the remodelling, inflammatory and neoangiogenic areas of the lungs of patients suffering severe asthma. This accumulation will then be observed using the imaging techniques previously described in order to obtain an early and accurate diagnostic and to envision cancer therapy performed in tumours by the radiosensitization of the same particles.

Lungs inflammatory diseases such as COPD are the cause of 2.5 M death worldwide. These diseases have in common a high influx of neutrophils that secrete proteases responsible for the progressive loss of lungs function. To date there is no method able to assess lungs enzyme activity in vivo. Such a method would allow an early diagnostic of any protease/inhibitor imbalance long before the detection of pulmonary lesions by anatomical imaging methods. Lungs function could thus be preserved with protease inhibitors. We propose a new proteolytic activity imaging method for the lungs using Overhauser-enhanced MRI (OMRI). We will take advantage of a world unique prototype device and of recently synthesized contrast agents. Method validation will be conducted with mouse models of emphysema and cystic fibrosis.

Nuclear Magnetic Resonance (NMR) has already proven to be a tremendous tool in –omics studies of Systems Biology, including the study of metabolome in biological systems known as metabolomics. Its major weakness is the low detection sensitivity that renders the analysis of microscopic quantities (submilligram) impractical, time consuming and often impossible. A cost-effective method is the use of micro(µ)-coils in NMR detections; however, implementing a NMR µcoil for heterogeneous samples such as tissues, cells and organisms is a challenging task. This is because of the necessity of spinning the sample at a 54.74° to the NMR magnetic field. This technique is known as Magic-Angle Spinning (MAS). The use of a spinning µcoil called High Resolution Magic Angle Coil Spinning (HRMACS) – developed by Alan Wong and his team at LSDRM marks the first successful µMAS NMR analyses of microscopic biospecimens, together with different biological expert-teams (INMG, ISA and CRMSB). Unfortunately HRMACS is greatly hindered by the impractical operation and the instability of µcoil. In 2015 without any financial supports, LSDRM has teamed up with a NMR-industry JEOL and developed an alternative technology, a standalone HRµMAS probe, specifically targeted to metabolomic applications. Unlike HRMACS, HRµMAS offers good metabolic analytical stability. However, further technological development and experimental validations are absolutely necessary in order for HRµMAS to have an impact in metabolomics. The aim of HRmicroMAS project is to implement and establish a truly convenient and accessible HRµMAS NMR-based application to the field of metabolomics. The project includes designing and constructing a stable HRµMAS probe, benchmarking and validating the HRµMAS NMR-based studies, and demonstrating its utilities with real applications. The success of the project will have a significant impact to the current NMR-platform for metabolomics, because it will be the first cornerstone of µMAS NMR-based metabolomics for microscopic specimens. The first half of the project will be dedicated to designing and building a reliable HRµMAS probe, and to benchmarking and validating the HRµMAS NMR experiments from sample-preparations to data acquisitions. The goal here is to develop a reliable HRµMAS NMR application that is convenient to everyone. The second half will carry out two independent pilot metabolomic studies with different teams whose are experts in metabolomic studies: (1) with the teams INMG and ISA, an metabolic investigation will be carried out on the heterogeneity of phenotype associated to aging within isogenic populations of Caenorhabditis elegans nematodes; and (2) with CRMSB, the metabolic profile of the brain energy metabolism in rat will be explored. These biological studies are designed to exploit and evaluate the different bioapplications of HRµMAS with different biological specimens, and will be an important milestone for HRmicroMAS, because it will demonstrate the wide utility of this innovative technology for NMR applications to in the field of metabolomics. HRmicroMAS fits well within the societal challenge #4 of “Life, Health and Well-Being” because it will be a vehicle that will lead to potential new discoveries and innovations in biological and medical science. And the strong collaborative nature in the multidisciplinary this project suits under the PRC financial instrument. It gathers µMAS experts (from LSDRM and JEOL), NMR spectroscopists (LSDRM and ISA) and biologists (INMG and CRMSB). This project also capitalizes a strong collaboration with a NMR industry, JEOL, whom will offer their involvements (probe design and construction) at zero-cost to the project. For this reason, HRmicroMAS can be considered a low-cost project (a requested fund of 304 k€) for a development of an innovative NMR application that could advance the analytical platform in metabolomics and open many new exciting venues.