Study of the impact of CFTR dysfunction on osteocytes (MucOsteocytes)

The life expectancy of people with cystic fibrosis (CF) continues to increase. CF-related Bone Disease (CFBD) affects nearly 50% of patients, but remains largely misunderstood, and the impact of aging on its development is not described. The MucOsteocytes program proposes to identify the impact of CFTR dysfunction on osteocytes. These cells, the most numerous in bone, are key players in tissue homeostasis. They derive from skeletal stem cells (SSCs) and represent the terminal stage of differentiation of the osteoblast lineage, whose function and maturation are altered in CF.

The objectives of this program are:

1) to study in vitro the impact of pharmacological inhibition of CFTR on the differentiation of human primary SSCs towards an osteocyte profile.

2) to decipher ex vivo, in CF F508delCftr and non-CF mice, the differences within the osteocytes lacuno-canalicular network, and the gene expression profiles of osteocytes in situ.

Cellular differentiation will be addressed in vitro using freshly isolated SSCs from bone marrow, treated or not with BPO-27 or Inh172, in a dedicated scaffold made specifically for this purpose. Cell samples characterization will include imaging approaches, molecular biology, analysis of protein expression... In order to be able to identify, in situ, an impact of CFTR on osteocytes, we will use bone samples from the F508delCftr mouse model and its wild-type counterpart, in two approaches for osteoporosis induction: a) ovariectomy-induced osteoporosis, and b) spontaneous osteoporosis linked to aging. The analyses will be carried out on tissue-cleared and stained samples to characterize the lacuno-canalicular network of osteocytes, enriched with a spatial transcriptomic analysis to identify variations in gene expression in situ. In vitro approaches will make it possible to determine the impact of CFTR in the cell differentiation processes occurring in bone tissue and to identify an altered differentiation of osteocytes, known to be the sentinels of bone tissue and whose survival and function are altered in contexts such as osteoporosis for example. We thus expect to update dysregulations of the gene expression profile, the number of osteocytes, the number of their extensions and, ultimately, their connectivity in CF animals. In vitro, because of previously evidenced osteoblast-defects, we expect that the loss of CFTR function delays the acquisition of a functional osteocyte phenotype. These data could provide a better understanding of the occurrence and maintenance of CFBD while promoting the detection of potential new biomarkers and therapeutic targets. MucOsteocytes program will make it possible to evaluate the association of physiological states (aging and menopause) and CFTR dysfunction on the osteocyte phenotype and on bone structure maintenance.

L’Unité de Recherche (UR) « Biomatériaux et inflammation en site osseux » est constituée d’enseignants-chercheurs et de praticiens hospitaliers (Odontologistes – Pharmaciens – Biologistes). Elle accueille également des personnels contractuels, post-doctorants doctorants et stagiaires. Le projet de recherche s’inscrit dans un cadre pluridisciplinaire et a pour objectifs de mieux comprendre la physiopathologie osseuse, via les interactions cellules/cellules, cellules/pathogènes et cellules/biomatériaux, en sites inflammatoire et/ou septique, afin d’élaborer de nouvelles biomatrices fonctionnalisées destinées au comblement osseux et d’évaluer leur potentiel régénératif.

Pour atteindre ces objectifs, l’UR 4691 conduit une recherche fondamentale visant à : 1) étudier la physiopathologie osseuse, notamment dans le contexte de maladies rares ; 2) améliorer les potentialités physico-chimiques et d’immunomodulation cellulaire des biomatrices pour optimiser leur cellularisation et leur fonctionnalisation ; 3) caractériser les processus biologiques (inflammation, infection, néoformation tissulaire…) influant sur les capacités régénératrices en site osseux.

Nos objectifs portent également sur des développements technologiques et méthodologiques : 1) évaluation de l’efficacité de nouveaux traitements pour les maladies à tropisme osseux ; 2) développement de nouvelles approches durables en régénération tissulaire ; 3) validation d’une méthode originale de stérilisation par plasma froid adaptée aux biomatrices préconditionnées.

Détenteur(rice) de bases solides en biologie cellulaire, vous faites preuve d’une apétence particulière pour les domaines de la physiopathologie osseuse et des maladies rares. Motivé(e) par les approches translationnelles, vous projetez de faire de la recherche votre métier et êtes désireux(se) d’évoluer dans un environnement mutli-disciplinaire et dynamique pour réaliser votre doctorat. Si vous vous reconnaissez dans la description ci-dessus, merci d’adresser CV et lettres de motivation et recommandation.

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With a solid knowledge in cell biology, you demonstrate a peculiar appetite for the fields of bone physiopathology and rare diseases. Motivated by translational approaches, you plan to make research your profession and you are eager to evolve in a mutli-disciplinary and dynamic environment to carry out your PhD program. If you recognize yourself in the description above, please send your CV and letters of motivation and recommendation.