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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

Linking synaptic dysfunction to disease mechanisms in schizophrenia - a multi-level investigation

Alternative title: Koble synaptisk dysfunksjon til sykdomsmekanismer i schizofreni - en multi-nivå studie

Awarded: NOK 4.8 mill.

Schizophrenia is a severely debilitating mental illness characterized by hallucination, delusions, cognitive disabilities and reduced functioning. It represents one of the major challenges for society, with large unmet patient needs and substantial health care costs to the European community. Over the past decade, it has become clear that schizophrenia is a disorder where different regions in the brain fail to communicate appropriately. In parallel, recent gene discoveries have pointed to dysfunctional communication of brain cells: the neurons. Together, these insights suggest that the connections between neurons in the brain - the synapses - are malfunctioning. However, the precise synaptic mechanisms leading to schizophrenia remain elusive. To this end, the SYNSCHIZ project formed a collaboration of experts from Norway, Germany, Switzerland, Finland, Romania and the Netherlands to study synaptic dysfunction at various levels from genes to neuron cells to brain networks using state of the art methodology. Research conducted as part of this project included (1) gene discoveries in large international samples, studying their link with large-scale brain networks, and further characterization of the association signals with reverse phenotyping approaches (2) computational modelling of synapses, and (3) experimental validation of the models in neuronal cultures, and (4) acquisition of clinical data that can be used for validation. As such, project partners jointly investigated disease patterns related to synapse dysfunction at all levels from genes to brain networks.

Prosjektet har ledet til ny kunnskap om sykdomsmekanismer ved schizofreni, som har blitt rapportert i 24 vitenskapelige publikasjoner. Dette har gitt ny kunnskap til forskningsfeltet. . Det norske delen av prosjektet har ledet til en doktor grad til ansatt stipendiat (under ferdiggjøring), og en pris til Dr. Kaufmann for beste artikkel. Gjennom den tverrfaglige prosjektet har vi etablert nye samarbeid på tvers av fagfelt som er bygget videre til ny forskningsprosjekt. Konsortimedlemmer har blitt med på flere felles søknader basert på samarbeid utviklet i prosjektet. Kunnskapen som er generert av prosjektet kan brukes til å utvikle ny behandling, spesielt bedre medikamenter, både mer effektive men også mindre bivirkninger. Det kan også hjelpe til med å finne bedre diagnostiske verktøy og legge grunnlag for mer presis behandling (presisjonsmedisin):

Schizophrenia (SZ) is a severe mental illness characterized by a wide range of defective cognitive function and a complex set of symptoms including hallucinations and delusions. SZ represents one of the major challenges for society, with large unmet patient needs and substantial health care costs for the European community. Various studies on the genetic risk architecture and aberrant brain functional connectome of SZ have implicated synaptic dysfunction in the pathophysiology, yet the precise mechanisms remain elusive. The complex nature of SZ can only be unveiled in an integrative, transdisciplinary research framework which involves several research disciplines collaborating on the same topic from different perspectives. To integrate and maximally exploit the transdisciplinarity benefits, the SYNSCHIZ project implements a vertical synergy approach, where synaptic dysfunction is targeted at multiple levels of investigation, from a genetic level to the neuron level to the level of brain network dysfunction. The vertical structure will maximize synergy by at four features: - identification of novel genes will improve the accuracy of computational models - experimental verification will allow refinement of the computational models - gene-level and neuron-level discoveries can be used to predict effects observable at brain level, - brain-level dysconnectivity discoveries can be used to link synapse dysfunction to symptoms. The multi-level approach aims to identify clinically useful biomarkers, required for early detection and prognostic predictions in SZ, e.g. by using pluripotent stem cells as a screening tool. SYNSCHIZ therefore implements a strong translational component that will immediately transfer scientific discoveries into clinical application for targeted treatment and care. To reach these ambitious aims, SYNSCHIZ gathers a consortium of international scientific experts, ensuring synergy across various disciplines and with access to critical infrastructure.

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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering