With expanding longevity, the number of dementia cases is increasing worldwide and is expected to triple over the next 40 years. Delaying the onset of dementia and Alzheimer disease (AD) by just a few years could have a major impact on their prevalence at the population level. To date no effective mechanism-based preventive strategies are available. Vascular risk factors (RFs) are modifiable and given the strong relationship between cerebrovascular disease and dementia they may offer an important opportunity for preventive approaches. Gathering evidence for and improving our understanding of associations between vascular risk and dementia is therefore of paramount importance. Several studies have shown that vascular RFs, especially hypertension, diabetes, and obesity, are associated with an increased risk of dementia, but findings are heterogeneous. In older age, measurements of RFs may be biased, due to comorbidities, concurrent medications, competing risk of mortality, etc. Moreover, clinical RF measurements are highly variable, and single measurements can lead to misclassification of an individual’s risk. Recently, genome-wide association studies (GWAS) have enabled the discovery of numerous common genetic variants associated with an increased risk of developing vascular RFs, stroke, and covert cerebrovascular disease. Although the effect of individual SNPs is usually small, their combined effect in a genetic risk score may be important. Genetic risk variants are not exposed to measurement variability; they can be detected early, in advance of clinically evident vascular RFs and disease, and may be better correlated with lifetime exposure to RFs than single late-life measurements of clinical RFs. Hence they could be useful for identifying individuals with a high risk of vascular-related cognitive decline and dementia that could be used in the future as a target population for testing early preventative interventions. We propose to utilize data from a large, richly phenotyped and densely genotyped ongoing French population-based cohort (3C Study), to explore associations of genetic markers for vascular risk with dementia, cognitive decline and structural brain aging. We suggest the following aims: (1) test associations of vascular genetic risk scores (VGRS) with incident dementia and cognitive decline; (2) test associations of VGRS with MRI-markers of structural brain aging known to be powerful predictors of dementia; (3) examine causality of associations between vascular RFs and dementia, cognitive decline, and structural brain aging using Mendelian randomization; (4) explore the clinical utility of VGRS in predicting dementia risk by testing the potential for risk discrimination and classification. We seek funding for statistical genetic and epidemiological analyses, genotyping of poorly imputed variants, server maintenance, blood measurements of continuous markers of vascular risk, and travels to facilitate collaborations. Extension of our findings will be sought, through independent funding, in the Framingham Heart Study. While it is evident that treating vascular RFs is necessary to reduce the burden of vascular disease, the impact of vascular RF treatments on dementia risk is unclear, as well as the optimal timing for intervention. If successful, information obtained from this project, combining cutting edge technology with genome-wide genotypes, as well as elaborate and innovative statistical and epidemiological models, could contribute to optimizing the design of future trials testing the impact of vascular RF treatments on dementia risk.

This "COSMIT" project focuses on a rare disease, the Costello syndrome (CS), the underlying mechanisms of which are not understood and for which no treatment is available. This rare disease is revealed in the first months of life and is characterized by postnatal growth retardation, thick lines, intellectual deficit and skin abnormalities, with muscle and heart alterations. Our aim is to elucidate the biological mechanisms responsible for this syndrome caused by a mutation (G12S) in the HRAS gene. Other less frequent mutations in this gene are the cause of rare diseases grouped under the term "rasopathies" as well as many cancers (HRASG12V). The fact that the French Association of Costello Syndrome and CFC based in Bordeaux has funded a novel mouse model of that disease (HRASG12S generated by the Mouse Clinical Institute) makes the context of this project particularly interesting, competitive and innovative. Indeed, we propose here to explore several facets of the pathophysiology of CS using this mice, but also skin fibroblasts obtained from patients, induced-pluripotent stem cells (iPSCs) and neural-crest derivatives. While current effort on the study of CS pathophysiology focus on the HRAS-related ERK signaling pathway, we discovered that HRAS constitutive activation in human fibroblasts inhibits the activity of both LKB1-kinase and its main target, the AMP-activated protein kinase (AMPK). This triggers both a metabolic reprogramming and an alteration of focal adhesion and cytoskeleton potientally involved in CS patophysiology notably during neural crest differentiation. Interestingly, the AMPK inhibition induced by HRAS can be reversed by using a pharmacological activator of AMPK, suggesting that a therapeutic approach could be derived from our observations. In addition, we explored the mice and found an alteration of muscle strength, locomotor activity, heart function, macrocephalia and hypertension. Further imaging analysis that are still ongoing confirmed the existence of potential cranio-facial changes in the mice that need to be further characterized. In addition, a transgenic mouse model of the cancer-associated HRASG12V mutation unexpectedly triggered the CS in mice, raising a fundamental question on the possible dose-effect of HRAS constitutive activation in Rasopathies, since the G12V mutation triggers a stronger biochemical activity of HRAS as compared to the G12S mutation. Therefore, we will compare the effect of those two mutations of HRAS on cell models, looking more closely at the impact on LKB1-AMPK and ERK signaling. We will perform an indepth analysis of HRASG12S mice through metabolic, cardiac and cognitive phenotyping and embryogenesis, with an emphasis on neural crest cells development. Since drugs are available to stimulate AMPK in human and mice, as resveratrol or AICAR, we will test their therapeutic effect on the mice model of CS. Inhibitors of RAS constitutive activation will also be tested as the Zopra cocktail developped by team 2. Lastly, we will evaluate the alteration of senescence in those mice and cell models of CS, since AMPK could regulate progerin levels via SRSF1 and because alteration in working memory was found in the HRASG12S mice and CS patients, a feature previously reported in patients with accelerated aging. Our project thus fits perfectly in the challenge "Health and Wellbeing" because we are studying the mechanisms of a rare disease on an original mouse model and patient-derived cell models, and we propose to evaluate two therapeutic approaches. We regrouped a consortium of internationally recognized experts in energy metabolism (R. Rossignol), mice generation and phenotypic characterization (Y. Herault) and rare diseases pathophysiology and therapy (N. Levy), along with a patient association to achieve the general aim of this project and disseminate our findings.

Cardiovascular diseases are responsible for 700 000 death each year in Europe, half of which are directly related to cardiac ventricular tachyarrythmias. Together with 6 million individuals suffering from atrial fibrillation, it has become a major burden for the people and the health care system in Europe. Cardiac modelling has evolved incredibly over more than 50 years, providing the most highly detailed mathematical description of any organ system in the body. Many fundamental insights have been gained from in-silico experiments. Cardiac electrical activity is determined by the molecular activity through the cell membrane that is organised at the tissue, organ, and body levels. Cardiac arrhythmias are complex disruptions of this organisation. Numerical models and fast dedicated solvers already exist that allow in-silico exploration of the mechanisms underlying these pathologies at the cost of large-scale simulations. The models are degenerate reaction-diffusion systems of equations coupled to stiff systems of differential equations, and the solvers are currently based on parallel first order robust though inaccurate techniques. However, current numerical models lack many important features. Due to their conceptual formalism, theydo not account properly for the heterogeneous microstructure of the tissue, nor for the multidimensional coupling between cardiac components. In addition, we have a very incomplete understanding of the numerical errors induced by the algorithms. Finally, validation of these numerical models is a very challenging, and open, research question. Numerical modelling plays an increasing role in the development of knowledge in cardiac electrophysiology but these issues limit the reliability of the models, and our capacity to explore in depth complex pathological mechanisms. The LIRYC institute provides an environment where modellers can efficiently interact with clinical and experimental researchers. Several members from LIRYC already associated with the Carmen team of applied mathematicians, and Pr Bourgault from the University of Ottawa, constitute the multidisciplinary group that will challenge the modelling, numerical and validation issues detailed above. All researchers are specialists in cardiac electrophysiology from the modelling, experimental or medical point of views. Based on this environment and new developments in structural and functional imaging of the heart available at LIRYC, we plan to reconsider the concepts behind the models in order to improve the accuracy and efficiency of simulations. Cardiac simulation software and high-resolution numerical models will be derived from experimental data from animal models. Validation will be performed by comparing of simulation output with experimentally recorded functional data. The validated numerical models will be made available to the community of researchers that take advantage of in-silico cardiac simulation and, hopefully, become references. In particular we shall provide the first exhaustive model of an animal heart including the four chambers coupled through the special conduction network, with highly detailed microstructure of both the atria and the ventricles. Such a model embedded in high-performance computational software will provide stronger medical foundations for in-silico experimentation, and elucidate mechanisms of cardiac arrhythmias.

The objective of the FUNGLASS project is to create a European network in the field of photonics and advanced photonic materials. The challenge is to achieve a scientific goal and to implement an innovative doctoral programme which will improve PhD’s training and foster their employability. The network will deploy a coordinated strategy and efficient working plan methodology in order to submit a proposal to the H2020-Marie Sklodowska-Curie European Training Networks (ETN) call (deadline 10 january 2017). The partnership will create collaboration across Europe between academic institution and industrial companies for the key enabling technology of photonics. The project will be coordinated by University of Bordeaux. The project FUNGLASS - FUNctional GLASS integration in photonics devices and components European Networking - addresses training, research and innovation in the design and manufacturing of optical components and systems. Among the materials used in photonics devices, glasses play a central role: they are used as laser sources, lenses, smart screen, fibers to name a few. Therefore, the research and development of glass- synthesis, shaping, functionalizing, processing and integration into device - is the positioned contribution of FUNGLASS. The challenging contribution of FUNGLASS relies on Local functionalization in glass by Laser writing or poling, offering extraordinary opportunity for fabrication of elementary bricks with unique topology, morphology and novel properties for the design of integrated multifunctional components and devices. Future developments require to address multiple properties issues such as transmission window, linear and nonlinear optical propagation of light, conductivity, surface chemical activity, photosensitivity, thermal and mechanical properties, etc. Furthermore, this R&D field requires to constitute a consortium of European partners with a very high degree of interdisciplinarity including physicists, chemists, material researchers from high-level research groups and process engineers from both SMEs and large Photonic companies. It is gathering unique expertise in glass design, local Laser/Field engineering controlled for functionalization in glass and integration in a component or device. The involvement of industrials guaranties the whole value chain from technology transfer to manufacturing and commercialization. The relevance of this project is to provide a highly synergetic combination of gathered scientific and technology expertise allowing to propose together future scientific collaborations for targeted applications, and PhD projects including mobility among the consortium (academic and industrial mobility will be proposed). The constituted network aims to be successful for European ETN project submission in January 2017. The ETN project will provide a unique training platform for doctoral research skills in glass-based components and systems for photonics. In addition to the scientific curriculum, the doctoral candidates will be trained in networking, communication and commercial exploitation, preparing them to be the highly skilled workforce in photonics which is penetrating many market sectors. The expected aid through ANR-MRSEI call is to facilitate exchanges between partners through the organization of workshops intended to refine the scientific proposal and the relevance of the training programme; to improve the relevance of the proposal within a H2020 call highly competitive; to enable the search for the most accurate industrial partners through the financing of market studies. The aid requested is € 29,160.