Project description
Insight into neuronal development offers cues for cell therapy
Parkinson’s disease (PD) is a progressive disorder of the central nervous system that affects mainly the dopaminergic neurons. Understanding the developmental pathways of these cells will provide a better insight into PD and cell-based therapies. The GRAIN project is funded by the Marie Skłodowska Curie Actions programme and aims to investigate the differentiation mechanisms of mesencephalic dopaminergic neurons. Researchers will focus on the gene regulatory networks implicated in this pathway as well as on Notch signalling. GRAIN results will help improve stem cell differentiation protocols and cell therapy approaches for PD.
Objective
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.
Fields of science
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- natural sciencesbiological sciencescell biology
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- medical and health sciencesbasic medicineneurologyparkinson
- natural sciencesbiological sciencesgeneticsgenomes
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
MSCA-PF - MSCA-PFCoordinator
1165 Kobenhavn
Denmark