H2020Индивидуална стипендия2017–2019

Schizophrenia Organoids · Understanding the role of parvalbumin interneuron development in schizophrenia using human cerebral organoids

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

Период: 2017-09-01 → 2019-08-31
Финансиране от ЕС: 178 157 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Развитието на специфични нервни клетки (парвалбумин интерневрони) се проучва чрез 3D модели на човешки мозък, създадени от стволови клетки. Това помага за разбирането на клетъчните причини за шизофренията, тъй като моделите от гризачи не отразяват точно човешката биология.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Understanding the role of parvalbumin interneuron development in schizophrenia using human cerebral organoids

Schizophrenia is a devastating psychiatric disorder with an unclear cellular etiology. Genome association studies have produced a large list of genes associated with Schizophrenia, but the ability to test the function of these genes in neurobiology remains hindered by a lack of human experimental models. This is exemplified by the fact that many differences in various aspects of cortical development exist between human and rodents, one currently preferred experimental system. The advent of 3D culture models that can be generated from human pluripotent stem cells has revolutionized the generation of disease models. Combined with the recent innovation of 3D brain organoid culture models, complex models of various brain disorders are now being developed. This provides the opportunity to assess the function of disease associated genes in complex cellular behavior in developing brain-like tissue. The goal of the current study was to generate a 3D human brain organoid model of schizophrenia. Since the GABAergic interneuron subtype is highly implicated in the pathogenesis of schizophrenia, a second aim focused on analyzing the development of human GABAergic interneurons in the 3D brain organoid schizophrenia model.

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

Цел на проекта

Neuropsychiatric disorders account for 1/5 of the total disease burden in Europe causing mental anguish and decreased quality of life for those affected, especially for schizophrenia patients. An intriguing theory suggests that altered brain development results in schizophrenia, and the selective cellular defects in parvalbumin (PV) inhibitory interneurons observed in schizophrenic patient brains. However, the role of altered interneuron development in producing these pathophysiological hallmarks of schizophrenia is currently unknown due to a lack of cellular models of human interneuron development. Cerebral organoids are a revolutionary in vitro model of embryonic brain development generating complex brain circuits and recapitulating many aspects of interneuron development. The generation of organoid tissue from hiPSCs allows for the growth of patient-specific brain tissue. Therefore, the current proposal will develop a cerebral organoid schizophrenia model to analyze PV-interneuron development. First, cerebral organoids will be grown from patient-derived hiPSCs genetically modified to include a PV-GFP reporter. Using this reporter, genome-wide PV-specific gene expression will be analyzed to identify deregulated developmental pathways during PV-interneuron development. Second, a phenotypic analysis of PV-interneuron development will determine how PV-interneuron synaptic morphology and/or migration are altered in this cerebral organoid schizophrenia model. These assays are relevant to disease-related pathology, and will include axonal morphological analysis and a novel organoid co-culture migration assay. These results will determine the role of interneuron development in the pathophysiology of neuropsychiatric disease for the first time in human tissue. Understanding the developmental mechanisms of schizophrenia will address a major unmet therapeutic need by inspiring new avenues of innovative therapeutic strategies.

Оригинален текст от CORDIS (на английски).

Участници

INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH · WienКоординаторАвстрия