Projektbeschreibung
De-novo-Proteine für die Knochenregeneration
Die erfolgreiche Regeneration von Knochengewebe zum Ersatz von Knochenverlusten stellt nach wie vor eine große klinische Herausforderung dar. Die Bemühungen konzentrieren sich auf die Gestaltung von Biomaterialien anhand biomimetischer Strategien, die Proteine aus der extrazellulären Matrix nutzen. Einige dieser Proteine enthalten Domänen, die in der Lage sind, Wachstumsfaktoren zu binden, wie z. B. die heparinbindende II-Domäne (HBII) von Fibronektin, die knochenmorphogenetische Proteine (bone morphogenetic proteins, BMPs) binden kann. BMP-2 ist ein starkes osteoinduktives Molekül. HBII fehlt es jedoch an der Spezifität für BMP-2. Im EU-finanzierten Projekt ENGAGE werden die Hotspot-Sequenzen identifiziert, die an der Interaktion zwischen HBII und BMP-2 beteiligt sind, und neue Proteine mit hoher Affinität zu BMP-2 entwickelt, um sie in Hydrogel-Biomaterialien zur Verbesserung der Knochenregeneration einzusetzen.
Ziel
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.
Wissenschaftliches Gebiet
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Koordinator
08034 Barcelona
Spanien