Description du projet
Diabète de type 2 et nouvelle stratégie pour évaluer le risque de fracture osseuse
Le diabète de type 2 (DT2) altère les propriétés matérielles intrinsèques de la matrice osseuse et, par conséquent, est associé à un risque de fracture trois fois plus important. Les techniques de diagnostic actuelles ne permettent pas de prédire la probabilité de fracture dans le DT2. La réticulation non enzymatique des protéines organiques, appelée accumulation de produits finaux de glycation avancée (AGE pour «advanced glycation end products»), serait responsable de la fragilité osseuse dans le DT2. Cependant, on ignore encore exactement comment des configurations protéiques modifiées altèrent la biomécanique de l’os entier. Le projet MULT2D, financé par l’UE, développe un cadre informatique associant le comportement moléculaire à l’architecture de l’os entier afin de découvrir les mécanismes physiques responsables de la fragilité osseuse chez les personnes diabétiques. Le projet établira une nouvelle stratégie pour l’évaluation clinique des risques de fracture.
Objectif
Type-2 (T2) Diabetes is associated with a 3-fold increase in bone fracture risk, despite the fact that bone volume is not reduced. This implies that T2 diabetes impairs bone quality, whereby the intrinsic material properties of the bone matrix are altered. However, current diagnostic techniques are unable to predict fracture probability in T2 diabetes as they are based on measures of bone quantity. While it is believed that non-enzymatic cross-linking of organic proteins (also known as AGE accumulation) in the bone matrix is responsible for bone fragility in T2 diabetes, there is a distinct lack of understanding how altered protein configurations impair whole-bone biomechanics. In this project, the applicant will embark on frontier research that will develop a state-of-the-art multiscale computational framework that couples behaviour from the molecular to whole-bone level, providing a basis to interrogate and elucidate the physical mechanisms that are responsible for diabetic bone fragility. A multiscale experimental framework will, for the first time, establish relationships between AGE crosslink-density and whole-bone fragility in animal and human T2 diabetic bone tissue. Together, this data will inform a probabilistic mutli-level model of hip fracture, which will be used to quantitatively evaluate the relationship between hip fracture probability, bone quantity and bone quality. The research programme will also establish a novel strategy for clinical fracture risk assessment that employs existing protocols to measure bone quantity, in combination with a surrogate measure of bone quality. The surrogate measure of bone quality proposed is a systemic measure of AGE content, which is clinically-obtainable through a blood sample and therefore widely-applicable. Overall, the project will provide a ground-breaking advance in our understanding of bone fragility, with remarkable potential to innovate novel solutions for clinical assessment of T2 diabetic bone disease.
Champ scientifique
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Programme(s)
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Régime de financement
ERC-STG - Starting GrantInstitution d’accueil
H91 Galway
Irlande