H2020Индивидуална стипендия2021–2023

PEDIATAX · Using patient-derived human induced pluripotent stem cells (hiPSCs) to interrogate disease mechanisms and treatment in spinocerebellar ataxias

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

Период: 2021-11-01 → 2023-04-30
Финансиране от ЕС: 168 700 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Стволови клетки от пациенти се използват за създаване на 3D модели на мозъка, за да се проучи генетичното заболяване SCA29. Това помага за разбирането на механизмите на болестта и търсенето на нови цели за лечение.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Using patient-derived human induced pluripotent stem cells (hiPSCs) to interrogate disease mechanisms and treatment in spinocerebellar ataxias

Spinocerebellar ataxias (SCAs) constitute a group of rare disorders that lead to progressive loss of motor coordination and movement as well as issues with speech and cognition. Determining their genetic aetiology is challenging due to the large number of genes involved. Furthermore, SCAs are predominantly incurable, and the development of novel treatment options has been hindered by a lack of appropriate disease models. The EU-funded PEDIATAX project proposes to generate human induced pluripotent stem cells (hiPSC) from SCA patients as well as isogenic hiPSC lines using CRISPR/Cas9-mediated genome editing, as a model for studying a SCA that affects children, spinocerebellar ataxia type 29 (SCA29). This early-onset genetic ataxia is associated with a significantly delayed development of motor skills and speech and causes cognitive deficits ranging from learning difficulties to intellectual disability. The pluripotent stem cells are differentiated into three-dimensional models, organoids, of the developing cerebellum to study disease mechanisms involved in SCA29. The research will focus on key factors implicated in the development of Purkinje cells known to play a role in the pathophysiology of SCA. The results will help determine SCA disease mechanisms and pave the way for the discovery of novel treatment targets in SCA29 and several other disorders that involve the mGluR1/IP3R1/TRPC3 calcium signalling pathway.

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

Цел на проекта

The proposed Fellowship unites a recently established patient cohort from Northern Finland with the extensive expertise of the host laboratory in investigating cerebellar disease to study spinocerebellar ataxias (SCAs), a heterogeneous group of incurable brain diseases defined by ataxia, or a loss of motor coordination. To date, genome wide analysis studies have associated >40 genes with driving SCAs. The vast clinical and genetic heterogeneity of the SCAs poses a significant challenge and as a result, no treatments are available for patients with SCA. Therefore, the need for novel treatment options or, at the minimum, suitable disease models, is urgent. The Fellowship aims to create disease-relevant cellular models of a subgroup of SCA using human induced pluripotent stem cells (hiPSC). These hiPSC lines have been derived from patients diagnosed with one of four SCAs (types 14, 29, 41 or 44), which are genetically distinct but may share common molecular disease mechanisms involving the mGluR1/IP3R1/TRPC3 signalling pathway. The project focuses on the IP3R1 receptor which regulates the development of Purkinje cells (PCs), the sole output neurons of the cerebellar cortex, and represents a convergent point in the pathomechanism of several ataxia disorders. To identify key disease mechanisms in this subgroup of SCAs, the hiPSCs will be differentiated into monolayer PCs and cutting-edge cerebellar organoids, which more fully recapitulate the cellular organisation of the cerebellum. The disease phenotypes will then be characterised using a combination of methods in biochemistry, molecular biology, visualisation and transcriptomics. Finally, we will adapt the differentiation protocol to a 96-well format to enable high-throughput drug screening. Ultimately, the proposed Fellowship aims to be the first study in Europe to use cutting-edge hiPSC differentiation protocols to interrogate disease mechanisms in SCA and set the stage for the discovery of novel therapeutic options.

Оригинален текст от CORDIS (на английски).

Участници

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD · OxfordКоординаторОбединеното кралство