Descrizione del progetto
Definire il meccanismo di aggregazione proteica nei disturbi neurodegenerativi
Le cellule svolgono la maggior parte dei processi biochimici negli organuli legati alla membrana o privi di essa. Prove recenti indicano che la separazione di fase liquido-liquido (LLPS, Liquid–Liquid Phase Separation) rappresenta il meccanismo chiave che porta le proteine a formare organuli privi di membrana. L’obiettivo del progetto InMIND, finanziato dall’UE, è comprendere in che modo la LLPS è coinvolta nei disturbi neurodegenerativi, in cui proteine intrinsecamente disordinate formano aggregati insolubili e provocano disfunzione neuronale e decesso. Il progetto scoprirà i fattori molecolari determinanti della LLPS e selezionerà i composti di piccole molecole che impediscono la formazione di condensati biomolecolari, aprendo la strada a strategie terapeutiche innovative per i disturbi neurodegenerativi.
Obiettivo
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.
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Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
1165 Kobenhavn
Danimarca