Description du projet
Développer des protéines de novo pour la régénération osseuse
La régénération réussie du tissu osseux en vue de remplacer des zones de perte osseuse représente toujours un défi clinique de taille. Des efforts en ce sens ciblent la conception de biomatériaux en recourant à des stratégies biomimétiques qui utilisent des protéines provenant de la matrice extracellulaire. Certaines de ces protéines contiennent des domaines capables de lier des facteurs de croissance, comme c’est le cas du domaine de liaison à l’héparine II (HBII) de la fibronectine, qui peut lier les protéines morphogénétiques osseuses (BMP). La BMP-2 est une molécule ostéo-inductive puissante. Toutefois, la HBII manque de spécificité pour la BMP-2. Le projet ENGAGE, financé par l’UE, identifiera les séquences clés impliquées dans l’interaction entre la HBII et la BMP-2, et développera des protéines de novo avec une affinité élevée pour la BMP-2 afin de les exploiter dans des biomatériaux à base d’hydrogel et améliorer la régénération osseuse.
Objectif
The successful regeneration of bone tissue to replace areas of bone loss in large defects remains a significant clinical challenge. Efforts have concentrated in the design of biomaterials using biomimetic strategies based on installing bioactivity at their surface using proteins from the extracellular matrix (ECM). Some of these ECM proteins contain domains capable of binding growth factors (GFs). This is the case of the Heparin Binding II (HBII) domain of fibronectin, which has the capacity to bind Bone Morphogenetic Proteins (BMPs). Among them, BMP-2 is known to be a potent osteoinductive molecule. However, the lack of specificity of HBII for BMP-2 limits its application. ENGAGE project aims to identify the hotspot sequences involved HBII-BMP-2 interaction and develop de novo proteins with high affinity to BMP-2 to further exploit them in hydrogel biomaterials for enhancing bone regeneration. To this end, HBII-BMP-2 will be co-crystallized to identify the sequences involved in the interaction. Based on these sequences, de novo mini-binders will be designed using Rosetta computational methodologies and optimized to have high-affinity to BMP-2. The osteoinductive capacity of the selected molecules will be analyzed and the optimal candidates will be used to functionalize hydrogel substrates. In this way, ENGAGE will open the possibility to obtain hydrogels able to sequester specific GFs from the extracellular fluids, avoiding the use of exogenous growth factors and their undesired side effects.
The candidate will be trained in new computational and lab skills for protein design under the supervision of a world leader in de novo protein design. These methodologies will be transferred to the Spanish research community for developing novel proteins for biomedical applications. In addition, the obtained skills in paper and project writing, management and leadership will have a strong impact in his competitiveness and the possibility to become an independent scientist.
Champ scientifique
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
08034 Barcelona
Espagne