H2020Индивидуална стипендия2021–2023

InMIND · Intervention in Neurodegenerative disorders via Mechanistic INsight into liquid-like Droplets

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2021-06-01 → 2023-05-31
Финансиране от ЕС: 219 312 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Биомолекулните кондензати в клетките и начинът, по който протеините в тях се групират, се анализират чрез нови компютърни модели. Това помага да се разбере как се образуват вредните натрупвания в мозъка при болести като Алцхаймер и как лекарства могат да ги предотвратят.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Intervention in Neurodegenerative disorders via Mechanistic INsight into liquid-like Droplets

Neurodegenerative diseases are a leading cause of dementia and death in the elderly population. With population aging and the lack of effective treatment, the number of individuals with dementia in EU28 is projected to double in the next 25 years. A hallmark of neurodegenerative diseases is the progressive accumulation of insoluble aggregates in the brain. While the path to the formation of these aggregates is still elusive, recent evidence suggests that they may in part originate from the dysregulation of biomolecular condensates. Biomolecular condensates are one of the ways cells compartmentalise and concentrate proteins, often together with nucleic acids, and are formed through a reversible de-mixing process which is often driven or aided by intrinsically disordered proteins and regions (collectively IDRs). In a new promising approach for therapeutic intervention, small-molecule drugs may be used to modulate the self-assembly process and material properties of condensates and prevent the formation of pathogenic aggregates. To substantiate the feasibility of this approach and guide the design of small-molecule modulators of condensate properties, we need molecular models which are able to accurately predict the influence of solution conditions and sequence variations on the preferences of IDRs to self-associate. In this project, we developed an unprecedentedly accurate and computationally efficient sequence-dependent model of IDRs and made use of the model to (i) interpret experimental data on the role of condensate formation and aberrant phase transitions in disease states, (ii) predict the effect of sequence variations and small molecules on the phase and rheological properties of condensates of IDRs, (iii) investigate the sequence dependence of Alzheimer's-related Amyloid-β42 self-association, and (iv) generate and analyse a database of the conformational ensembles of all the IDRs in the human proteome.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

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.

Оригинален текст от CORDIS (на английски).

Участници

KOBENHAVNS UNIVERSITET · KOBENHAVNКоординаторДания