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Gene Regulatory Network Architecture in Neuronal Development
Stem cell-based therapy is an attractive way to treat a panel of as-yet incurable diseases, amongst which is Parkinson’s Disease, caused by the progressive degeneration of mesencephalic dopaminergic (mesDA) neurons. To make this a... Stem cell-based therapy is an attractive way to treat a panel of as-yet incurable diseases, amongst which is Parkinson’s Disease, caused by the progressive degeneration of mesencephalic dopaminergic (mesDA) neurons. To make this a reality, efficient and precise differentiation protocols of human embryonic stem cells (hESCs) need to be developed. While a protocol for differentiation of mesDA neurons exists, little is known about the resulting progenitors’ homogeneity and the mechanisms that control their maintenance, expansion and differentiation. MesDA neurons arise from ventral midbrain progenitors, whose differentiation requires the transcription factor Neurogenin 2 (NGN2). NGN2 acts as a master regulator by binding to, and stimulating transcription of, a panel of poorly defined target genes, while itself negatively regulated by HES1, one of the main effectors of Notch signalling. Yet, the involvement of Notch signalling in mesDA differentiation and the composition of the HES1/NGN2 gene regulatory network (GRN), i.e. the group of genes under their transcriptional control, in this context remains largely unknown. The aim of this action is to determine the mechanisms by which HES1, NGN2 and their GRN control mesDA differentiation. Building upon and expanding existing tools and knowledge in the host lab, I will use a multidisciplinary approach combining genome editing and hESC biology to derive mesDA progenitors from a panel of wildtype and HES1/NGN2 KO hESCs cell lines, with a multiomics approach to define the members of the HES1/NGN2 GRN and unravel its mechanism of action. The synergy between the expertise of the host lab in developmental and stem cell biology, and my extensive knowledge of bioinformatics and experience in the generation of multiomics datasets, will allow to both improve the efficacy and quality of the current mesDA differentiation protocols, as well as expand fundamental knowledge about the architecture of GRNs regulated by Notch signalling. ver más
31/08/2025
UCPH
215K€
Perfil tecnológico estimado
Duración del proyecto: 37 meses Fecha Inicio: 2022-07-14
Fecha Fin: 2025-08-31

Línea de financiación: concedida

El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2022-07-14
Línea de financiación objetivo El proyecto se financió a través de la siguiente ayuda:
HORIZON-MSCA-2021-PF-01-01: MSCA Postdoctoral Fellowships 2021
Cerrada hace 3 años
Presupuesto El presupuesto total del proyecto asciende a 215K€
Líder del proyecto
KOBENHAVNS UNIVERSITET No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico TRL 4-5