Projektbeschreibung
Untersuchung des Mechanismus der Proteinaggregation bei neurodegenerativen Erkrankungen
Der größte Teil der biochemischen Prozesse in Zellen findet in membrangebundenen oder membranlosen Organellen statt. Jüngste Erkenntnisse deuten darauf hin, dass die Flüssig-Flüssig-Phasentrennung der Schlüsselmechanismus ist, der Proteine dazu bringt, membranlose Organellen zu bilden. Das EU-finanzierte Projekt InMIND untersucht, inwieweit die Flüssig-Flüssig-Phasentrennung bei neurodegenerativen Erkrankungen eine Rolle spielt, bei denen intrinsisch ungeordnete Proteine unlösliche Aggregate bilden und zu neuronaler Dysfunktion und damit zum Tod führen. Das Projekt wird die molekularen Determinanten der Flüssig-Flüssig-Phasentrennung aufdecken und niedermolekulare Verbindungen untersuchen, welche die Bildung von biomolekularen Kondensaten verhindern und damit Wege für innovative therapeutische Strategien bei neurodegenerativen Erkrankungen eröffnen.
Ziel
With population ageing and the lack of effective treatments, neurodegenerative diseases (NDs) are expected to pose an increasingly severe challenge to healthcare systems worldwide. A hallmark of NDs is the presence of insoluble aggregates of intrinsically disordered proteins (IDPs) and proteins with disordered regions in neuronal cells. Growing evidence suggests that these disease-associated proteins condense into liquid-like droplets through liquid-liquid phase separation (LLPS). Dysregulation of this process results in the maturation of the liquid-like droplet into a dynamically arrested state, promoting the formation of putatively neurotoxic oligomers and amyloid fibrils.
In this project, I will first develop a molecular model that accurately predicts LLPS of IDPs from amino acid sequence and solution conditions. Second, through large-scale simulations of IDPs, I will elucidate the influence of mutations and post-translational modifications on the material properties of protein condensates. Third, I will employ the model to identify small molecules that preferentially partition into the protein-dense phase and enhance the dynamics of the protein network of the condensate. My findings will shed light on the molecular determinants of LLPS and contribute to explore an innovative therapeutic strategy for NDs, wherein small-molecule compounds prevent aberrant liquid-to-hydrogel-like transitions of biomolecular condensates. The project will enable me to apply my expertise in physical chemistry to therapeutically-relevant biological systems, acquire new competencies in chemoinformatics and project management, and establish myself as a high-quality researcher in the field of biomolecular condensates. The group of Prof. Kresten Lindorff-Larsen in the SBiN-Lab section at the University of Copenhagen will provide an excellent environment with world-leading experts in integrative structural biology and biophysics.
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Aufforderung zur Vorschlagseinreichung
Andere Projekte für diesen Aufruf anzeigenFinanzierungsplan
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Koordinator
1165 Kobenhavn
Dänemark