HEИндивидуална стипендия2023–2025

Protambbody · Proteasomal degradation of toxic intracellular amyloid-beta protein by nanobody-enabled proximity to ubiquitin ligase

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

Период: 2023-01-01 → 2025-06-30
Финансиране от ЕС: 269 418 €
Участници: 2
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Човешки неврони, създадени от стволови клетки, се използват за проучване на начина, по който клетъчната система за изхвърляне на отпадъци разгражда токсичния протеин амилоид-бета. Това помага за разбирането на механизмите на болестта Алцхаймер и търсенето на нови терапии.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Proteasomal degradation of toxic intracellular amyloid-beta protein by nanobody-enabled proximity to ubiquitin ligase

Alzheimer’s disease (AD) is the most prevalent form of dementia as well as the most common neurodegenerative disorder affecting the general public in both Europe and the world. It is also a major cause of disability and death especially in the elderly and currently has no cure. There are over 10 million new cases of dementia each year worldwide (up to 80% of which are due to AD), implying one new case every 3.2 seconds. In Europe, about 10 million people currently suffer from this disease and about 50 million in the world; with these estimates projected to double by 2050. Thus, the identification of novel disease-modifying therapies has become very critical to eradicating AD from Europe and the world. The disease is believed to be caused by the accumulation of a protein called amyloid beta (Aβ) in the brain. Most clinical trials of therapeutic interventions for AD have failed due to a lack of effective models and an inadequate understanding of the mechanisms underlying the disease process. Importantly, because the etiology of AD is unknown, it is currently impossible to model it appropriately using the popular transgenic models that entail genetic manipulations. Thus, the Protambbody project proposes to model Aβ-associated AD pathology in vitro using human neurons differentiated from induced pluripotent stems cells (iPSCs) reprogrammed from somatic cells of adult human subjects suffering from AD. Using these human iPSC-derived brain cells, Protambbody was designed to investigate a key cellular waste disposal machinery called the ubiquitin proteasome system (UPS) in AD and further manipulate this system to degrade Aβ aggregates being the causative agent of AD.

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

Цел на проекта

The amyloid-beta (A) protein arises from the sequential proteolytic cleavage of A precursor protein (APP). The accumulation of A oligomers has been regarded as the causal factor of Alzheimers disease (AD). Basal metabolic production of the A peptide is typical in healthy people, and its production rate is normally lower than its rate of clearance. In AD, the uncontrolled accumulation of toxic forms of A stemming from problems in its clearance and degradation results in memory loss, chronic neuroinflammation and neurodegeneration. AD is a leading cause of disability and death both in Europe and the world, and currently has no cure or clinically-proven disease-modifying therapies. There are over 10 million new cases of dementia each year worldwide (up to 80% of which are due to AD), implying one new case every 3.2 seconds. In Europe, about 10 million people currently suffer from this disease and about 50 million in the world; with these estimates projected to double by 2050. Thus, the identification of novel disease-modifying therapies has become very critical to eradicating AD from Europe and the world. My project proposes a radically novel approach in the AD field of utilizing the bodys cellular waste disposal system to selectively degrade A peptide, the causative agent of AD. This is in sharp contrast to the current approach of immunization against the A peptide, which has repeatedly failed to yield any cure or disease-modifying therapies for AD.This project will aim to identify the specific cytotoxic A peptides responsible for neuroinflammation and neurodegeneration in human induced pluripotent stem cells and target these peptides for degradation by the ubiquitin proteasome system. Emphasis will be on the cytotoxic A peptides of intracellular origin as emerging targets in AD. This research will be conducted at the University of Helsinki, Finland, followed by a non-academic placement at Roche Diagnostics GmbH.

Оригинален текст от CORDIS (на английски).

Участници

HELSINGIN YLIOPISTO · HelsinkiКоординаторФинландия
ROCHE DIAGNOSTICS GMBH · MannheimГермания