Descripción del proyecto
El desarrollo de proteínas «de novo» para la regeneración ósea
La regeneración eficaz del tejido de los huesos para reemplazar zonas de pérdida ósea sigue siendo un gran desafío clínico. El método actual consiste en diseñar biomateriales con la ayuda de estrategias biomiméticas que emplean proteínas de la matriz extracelular. Algunas de las proteínas contienen dominios capaces de unir factores de crecimiento, como ocurre con el fragmento de unión a la heparina (HBII) de la fibronectina, que puede unir proteínas morfogenéticas óseas (BMP). La BMP-2 es una potente molécula osteoinductiva; sin embargo, el HBII carece de especificidad para la BMP-2. El proyecto ENGAGE, financiado con fondos europeos, identificará las secuencias principales relacionadas con la interacción entre el HBII y la BMP-2, y desarrollará proteínas «de novo» con un gran nivel de afinidad a la BMP-2 para expandir su uso en biomateriales de hidrogel, a fin de aumentar la regeneración ósea.
Objetivo
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.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
08034 Barcelona
España