Description du projet
Dévoiler l’étiologie moléculaire de la schizophrénie
Des données de plus en plus nombreuses laissent entendre que la schizophrénie naît de perturbations rencontrées au cours du développement du cerveau. Les données indiquent que les symptômes sont causés par différents changements pathologiques dans les neurones excitateurs, la microglie et les oligodendrocytes. Le projet SCHIZTYPE, financé par l’UE, part de l’hypothèse que les cellules excitatrices développent des modifications génétiques dans les gènes à risque de schizophrénie et finissent par provoquer des modifications dans d’autres types de cellules. Les chercheurs étudieront les réseaux de régulation génétique spécifiques à un type de cellule dans les neurones excitateurs, ainsi que l’impact fonctionnel sur d’autres types de cellules. Les résultats du projet pourraient expliquer les multiples pathologies cellulaires observées dans la schizophrénie et dévoiler l’étiologie moléculaire de la maladie.
Objectif
Schizophrenia is a heritable but genetically complex disease. Pathological and epidemiological data fit a model of SCZ as a network disease with perturbations during brain development leading to early-adulthood onset clinical symptomatology. Our present understanding is based on single markers or arrays of gene expression from tissue samples containing multiple cell types. As a consequence, pathological changes in the function of inhibitory or excitatory neurons, microglia, or oligodendrocytes have variously been proposed to be the cause of symptoms. In light of recent data I hypothesize that it is unlikely that the various cellular SCZ-pathologies all arise independently from genetic alterations in multiple cell types. Recent findings from my lab show that in the cortex the expression of risk genes for SCZ are enriched in excitatory neurons, and that this set of risk-genes is largely non-overlapping with those expressed in other cell types. I propose that pathological genetic changes in excitatory cells ultimately initiates pathological changes in other cell types contributing to the multiple cellular pathologies observed in SCZ. We will:
1. Identify cell type-specific gene regulatory networks involved in SCZ (SCZ-GRNs) in prefrontal cortical excitatory cells by analysis of four distinct SCZ mouse models.
2. Confirm putative SCZ-GRNs in patient material using in situ transcriptomics on postmortem brains and connect to clinical features via collaboration with genomic studies in Sweden and Denmark.
3. Functionally investigate the effects of perturbing excitatory cell SCZ-GRNs on other cell types.
Single-cell RNA-seq, providing insights into the molecular properties of individual cells, and modern molecular tools for perturbing transcription in a cell type-specific way opens up for new knowledge of mechanisms underlying SCZ pathology. My work will identify causal relationships that can be exploited for the development of strategies for personalized treatment.
Champ scientifique
Mots‑clés
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
17177 Stockholm
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