Projektbeschreibung
Neue Wirkstoffklasse von Gefrierschutzmitteln auf Basis von Polymerproteinen
Für die langfristige Lagerung lebensfähiger Zellen und Gewebe als therapeutische Wirkstoffe in der regenerativen Medizin sind wirksame, nicht-toxische Gefrierschutzmittel unerlässlich. Die Biopolymere, die als eisbindende Proteine bekannt sind, können Schädigungen durch Einfrieren verhindern, indem sie die Keimbildung und das Wachstum von Eiskristallen kontrollieren. Das EU-finanzierte Projekt PROTECT zielt darauf ab, modulare Biopolymere zu entwickeln, um die quantitativen physikalisch-chemischen Experimente durchzuführen, die erforderlich sind, um zu verstehen, was die Aktivität von Biopolymere als Inhibitoren von Gefrierschädigungen auf Einzelmolekülebene bestimmt, und um die Kryokonservierung zu optimieren. Ziel ist es, eine neue Klasse eisbindender Proteinpolymere zu synthetisieren und mithilfe der superauflösenden Mikroskopie ihre Auswirkungen auf die Kryokonservierung von Zellen und Gewebe des menschlichen Herzens zu untersuchen.
Ziel
Efficient, non-toxic cryoprotectants, that allow long-term storage of viable therapeutic cells and tissues, are the tool that regenerative medicine requires for its successful realization into a viable therapeutic option. A remarkable class of biopolymers known as ice-binding proteins (IBPs) alleviate the risk of freeze injury throughout the Kingdoms of Life by keeping the nucleation and growth of ice crystals in check. Yet, the application potential of IBP analogues (IBPAs) as cryoprotectants has remained underexploited. This is because we are yet to unravel and utilize the structure-function relations, which govern the activity of IBPAs as inhibitors of ice recrystallization and promoters of ice nucleation at the single-molecule level in vitro and within a complex biological environment.
I propose to develop uniquely modular IBPAs to perform the quantitative single-molecule and physico-chemical experiments essential to bridge this knowledge gap and to engineer ice-binders optimized for cryopreservation. Our first aim is the biosynthesis of a novel class of ice-binding protein-polymers (iPP) with systematic variations in composition and size. Ice nucleators with a broad range of sizes will be created from iPPs of variable chain length by dissolution, self-assembly and surface-tethering to nanoparticles of variable dimensions. Super-resolution microscopy experiments of iPP ice-binding will deliver high-resolution maps of spatiotemporal distribution and dynamics. These will be related to iPP structure, physico-chemical properties, ice recrystallization inhibition (IRI) and ice nucleation (IN) activity. These insights will translate into the next generation of bioactive iPPs tailored to maximize both IRI and IN. Their impact on heart cell and tissue cryopreservation will be examined to advance our fundamental understanding of freeze injury and dramatically improve post-thaw recovery as well as structural and functional integrity without adverse effects.
Wissenschaftliches Gebiet
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-COG - Consolidator GrantGastgebende Einrichtung
5612 AE Eindhoven
Niederlande