Descrizione del progetto
Lo sviluppo di proteine ex novo per la rigenerazione ossea
La rigenerazione efficiente dei tessuti ossei per sostituire le zone caratterizzate da perdita ossea si conferma una sfida clinica rilevante. Gli sforzi si concentrano sulla progettazione di biomateriali avvalendosi di strategie biomimetiche che impiegano proteine provenienti dalla matrice extracellulare. Alcune di queste proteine contengono domini capaci di legare i fattori di crescita, come nel caso del dominio di legame dell’eparina II (HBII) della fibronectina che è in grado di legare le proteine morfogenetiche ossee (BMP, Bone Morphogenetic Protein). BMP-2 è una potente molecola osteoinduttiva; tuttavia, HBII non è specifica per BMP-2. Il progetto ENGAGE, finanziato dall’UE, individuerà le sequenze dei punti critici coinvolti nell’interazione tra HBII e BMP-2, sviluppando inoltre proteine ex novo dotate di una forte affinità con BMP-2 per sfruttarle ulteriormente nei biomateriali idrogel al fine di migliorare la rigenerazione ossea.
Obiettivo
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.
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Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
08034 Barcelona
Spagna