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Liquid liquid phase separation mediated protein fibrillation leading to neurodeg...

Liquid liquid phase separation mediated protein fibrillation leading to neurodegenerative diseases Neurodegenerative disorders are the leading cause of physical and cognitive disability, currently affecting ~15% population worldwide with estimated global cost of healthcare accosiated with them expected to at least double in the... ver más

31/05/2027

171K€

Presupuesto del proyecto: 171K€

Líder del proyecto

UNIVERZA V MARIBORU No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Financiación concedida El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2024-05-12

Línea de financiación objetivo El proyecto se financió a través de la siguiente ayuda:

HORIZON-MSCA-2023-PF-01-01: MSCA Postdoctoral Fellowships 2023

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Últimas noticias

29-11-2024: IDAE En las últimas 48 horas el Organismo IDAE ha otorgado 4 concesiones

29-11-2024: ECE En las últimas 48 horas el Organismo ECE ha otorgado 2 concesiones

29-11-2024: CMVAMADRID En las últimas 48 horas el Organismo CMVAMADRID ha otorgado 37 concesiones

Duración del proyecto: 36 meses Fecha Inicio: 2024-05-12
Fecha Fin: 2027-05-31

Líder del proyecto

UNIVERZA V MARIBORU

TRL 4-5

Presupuesto del proyecto 171K€

Descripción del proyecto Neurodegenerative disorders are the leading cause of physical and cognitive disability, currently affecting ~15% population worldwide with estimated global cost of healthcare accosiated with them expected to at least double in the next 20 years. Five most common neurodegenerative diseases, including ALS and FTD, are linked to formation of protein deposits in patient tissues and are currently without treatment options that would prevent or alter the disease progression. ALS and FTD pathology is characterised by accumulation and formation of insoluble protein deposits formed by proteins, like TDP-43, FUS and DAXX. These proteins undergo liquid-liquid phase transition (LLPS) in cells forming non-membrane bound organelles, which are important in RNA processing and stress responses of cells but their dysregulation acts a precursor to protein fibrillation. In this project we will, therefore, combine traditional biophysical approaches with modern molecular dynamics simulations and solution state nuclear magnetic resonance to discern this complex behaviour leading to LLPS, and gain molecular insight into its onset. Major outcomes of the project are (1) Develop the necessary simulation tools by reparametrizing currently available force fields using experimental data; (2) Apply the simulation tool and analytical methods to interactions between oligonucleotides and ions with proteins and compare results to experimental data; (3) Map phases and coacervation of DAXX in the presence of nucleotides and ions; (4) identify residues crucial for fibrillation and determine their role in cellular LLPS; (5) Apply high-throughput virtual screening to design proteins aggregation breaking ligands with therapeutic potential Outcomes of this project will importantly enhance our understanding at a mechanistic level, the role of these factors in promoting LLPS in cell biology.

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