Descripción del proyecto
Desvelar la etiopatogenia molecular de la esquizofrenia
Numerosos indicios señalan que la esquizofrenia aparece como resultado de perturbaciones durante el desarrollo encefálico. Los datos indican que los síntomas son provocados por diferentes cambios patológicos en las neuronas excitadoras, las células de la microglía y los oligodendrocitos. El proyecto financiado con fondos europeos SCHIZTYPE trabaja con la hipótesis de que las neuronas excitadoras adquieren cambios genéticos en genes de riesgo de la esquizofrenia y, en último término, inducen cambios en otros tipos celulares. Sus investigadores estudiarán redes reguladoras de genes específicos del tipo celular en neuronas excitadoras y examinarán el impacto funcional en otros tipos de células. Los resultados del proyecto podrían explicar las múltiples afecciones celulares observadas en la esquizofrenia y desvelar la etiopatogenia molecular de esta enfermedad.
Objetivo
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.
Ámbito científico
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Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
17177 Stockholm
Suecia