The present project aims to assess a novel approach to promote the osteogenic differentiation of mesenchymal stem cells for bone healing and regeneration in patients with large bone defects and those with reduced number of osteocompetent cells. Although these cells are considered as a valuable source for bone tissue regeneration, their capacity to differentiate along functional bone forming osteoblasts remains relatively limited in vivo. An important issue for efficient bone regeneration is therefore to target hMSCs to promote their osteogenic potential. P. Marie’s team has recently shown that forced expression of the a5 integrin subunit (ITGA5) or priming ITGA5 integrin using specific agonists induces osteoblast gene expression and osteogenic differentiation of cultured human MSCs (hMSCs). We also showed that forced expression of ITGA5 in hMSCs results in a marked increase in de novo osteogenesis in vivo, trevealing a critical role for ITGA5 in osteogenic differentiation of adult human mesenchymal stromal cells. In this project, we will evaluate the potential of promoting the osteogenic potential of mesenchymal stem cells in vitro and in vivo by targeting ITGA5. To this goal, Partner 1 (Institut de Recherches Servier) will first use chemical and molecular modeling methods based on structural homology models to develop new non-peptidic entities that can mimic the existing ITGA5 agonist, the cyclic CRRETAWAC peptide. Partner 1 will also be in charge of the identification of novel analogues (peptidomimetics and heterocyclic compounds) that activate ITGA5, through SAR (structure-activity relationship) studies on the cyclic CRRETAWAC peptide, in silico modeling of its interaction with the alpha5beta1 integrin, and in silico screening of selected chemical libraries and evaluation of hits in molecular assays. Partner 2 (P. Marie’s Team, Inserm U606) will be in charge of testing ITGA5 agonists developed by partner 1 in functional tests in hMSCs. To this goal, partner 2 will select ITGA5 agonists having the most positive stimulatory effect on FAK/ERK/PI3K signaling that activates MSC osteogenic differentiation and that promote markers of osteoblast differentiation and osteogenic differentiation in murine and human MSCs in vitro. A limited number of these molecules will be then tested for their capacity to promote bone formation in vivo using two models, a standard ectopic model in the mouse and an animal model of senile osteoporosis which exhibits low bone mass, impaired bone formation and decreased osteoblastogenesis. These animals will be treated with appropriate amount of ITGA5 agonists delivered locally or systematically and the effects on osteogenesis will be assessed by quantitative histomorphometry and microCT analysis. The success of the project will be based on the tight coordination between various disciplines (chemistry, modelisation, pharmacology, biology, histology) and on the combined expertise of one recognised academic laboratory in bone biology (MSCs and osteogenesis) and a pharmaceutical company that has a strong expertise in pharmacology of integrins and has developed a successful therapeutic strategy in osteoporosis.

Depressive disorders have a lifetime prevalence of 10-25% with increasing incidence in older people. Depression accounts for 4.4% of the years lived with disability worldwide, and is expected by 2020 to be the second highest cause of morbidity. Despite significant advances in the understanding and treatment of depression, its causes and molecular basis are still poorly understood and there exists a need to develop more efficient and better-tolerated antidepressants. In 2010, a novel antidepressant, Agomelatine (Valdoxan) has been introduced on the market. Clinical trials have shown that favorable features of agomelatine are fast onset of the therapeutic effect and the absence of major side effects. This compound represents a novel class of antidepressant as it is the first drug that targets melatonin MT1 and MT2 receptors (agonistic properties) and 5-HT2c receptors (antagonistic properties) all belonging to the G protein-coupled receptor (GPCR) super-family. The unique activity profile of Agomelatine apparently depends on both, the melatonineric and the serotoninergic components. However, the molecular mechanism of this “cross-talk” is currently unknown. In recent years a lot of evidence has accumulated that GPCRs can form homo- and heteromers. Increasing evidence shows that GPCR heteromers can be considered as a distinct functional entity with pharmacological and functional properties different from those of the corresponding homomers. Interestingly, several examples in the literature describe the implication of heteromers in psychiatric disorders. Because of the unique bifunctional profile of Agomelatine (melatonin receptor agonist and 5-HT2c receptor antagonist), we hypothesized that Agomelatine might target MT1/5-HT2c or MT2/5-HT2c heteromers and may be responsible for their antidepressant effects.

Proteins dictate virtually all cellular processes. To do so, precise 3D-structures that fit to their binding partners are exploited. However, up to 40% of the human proteome exist in disordered, dynamic ensembles of states mandatory for function. These so-called intrinsically disordered protein and regions (IDPs) play crucial roles in most aspects of life. They mediate tens of thousands of protein-protein interactions involved in cell signaling, scaffolding, transcription, membrane-less organelles and more. While the pivotal role of IDPs in biology is recognized, most of their functions remains unexplored. The time is now ripe for the next frontier, decomposing protein-protein interactions involving IDPs on a large scale. Importantly, IDPs are emerging drug targets for treating complex diseases: cancer, neurodegenerative disorders, metabolic syndromes and viral diseases, afflicting an ageing European population. The evolving field demands a new generation of experts to take the lead in developing different types of drugs targeting IDP interactions. This MSCA DN project aims to educate ten doctoral students within this evolving field by tackling outstanding questions. In particular, we will delineate the role of context in interactions involving IDPs, including flanking regions, folded domains, disease-related mutations, and aberrant cellular signaling and also design peptide-based ligands based on disordered regions that can potentially be further developed into drugs or molecular probes. A team of 14 established scientists from seven academic institutes and five companies, with excellent experience in supervision and cutting edge knowledge on IDPs and experimental and computational techniques will form IDPro. IDPro constitutes an exceptional network where the PhD students can mature and obtain scientific excellence in academic as well as non-academic settings. IDPro will strengthen the future academic and biotech labor force of the European union.

Two of the major hurdles for the chemical industry transition toward the “chemical factory of the future” are the ability to design (i) efficient and selective catalytic transformations of renewables and (ii) eco-efficient separation processes to retrieve and purify the product(s) and catalyst(s). Future generations of researchers (academic &industry) will need to be trained and equipped with these expertise that constitute the main goal of ChimSep. ChimSep aims at establishing an inter-disciplinary and inter-sectoral European Joint Doctorate programme offering challenging and innovative research and training in sustainable catalytic synthesis and sustainable membrane separation processes. The network is based on 7 academics, 7 industrials partners and 1 bio-economy cluster. Such a network gathering internationally renowned experts in the two topics has never been built-up and carried in Europe. ChimSep will implement an unprecedented and high-level training programme in order to provide the 13 Doctorate Candidates (DC) with a double culture/competency in both chemical synthesis and membrane separation. The capability of future European researchers to work at the interface of different domains and to master the entire process chain is a key to increase the competitiveness of European chemical research and industry by the progressive replacement of distillation by membrane processes at least 10 times less energy consuming. Each DC will benefit from training through a research project conducted in two academic sites plus a secondment in industry. DCs will acquire complementary soft skills provided during network events, interdisciplinary summer schools, workshops and a collective research project. All DCs will be hosted few months by industrials. Furthermore, ChimSep has designed an innovative supervision policy to favour fruitful exchanges between DC and senior scientists providing an exceptional training experience, through extensive research and complementary skills development.