- Bundesministerium für Bildung und Forschung (BMBF)
- Deutsches Zentrum für Luft- und Raumfahrt e.V. (DLR)
The overall project aims at the development of a predictive test system for compound profiling based on induced pluripotent stem cells (IPSC) derived from schizophrenic as compared to autistic patients.
Schizophrenia is a devastating illness affecting up to 1% of the world population (Nature Rev. Neurosci. (2005) 6:312). Beside the elaboration of positive (delusions, perceptual disturbances, hallucinations etc.) and negative symptoms (asociality, anhedonia, alogia, impaired decision-making, cognitive deficits etc.) patients suffer from increased risk for drug abuse and comorbid depression resulting in suicide in about 5-10% of the cases (J. Clin. Investig. (2009) 119:706). Therefore schizophrenia is linked to substantial emotional burdens for patient families as well as very high economic costs both in terms of medical expenditure and lost productivity. Asperger-Autism is considered a disorder of neural development characterized by impaired social interaction and the development of restricted, repetitive patterns of behaviour, interests and activities. It is accompanied by alterations in synaptic connectivity.
While specific pharmacotherapies for Asperger-Autism are lacking, present therapeutic approaches in schizophrenia mainly focus on the modulation of dopaminergic transmission (Mol. Psych. (2005) 10:79). Further approaches refer to impaired NMDA receptor activity which led to the introduction of phencyclidine (PCP) models. However, available therapeutic interventions ameliorate positive symptoms to a certain degree but fail with negative, most probably due to the mostly unknown etiology of schizophrenia. New trends in the field aim at the level of signal transduction emerges (Mol. Psych. (2005) 10:79) and the integration of aberrant neurodevelopment. Such novel therapeutic approaches require completely different experimental models and drug screening processes which are not available so far. To meet these demands we plan a novel drug screening platform:
The overall project aims at the development of a predictive test system for compound profiling based on induced pluripotent stem cells (IPSC) derived from schizophrenic as compared to autistic patients. This will be achieved by:
1. Establishment of human patient-derived neurons from IPSCs
2. Establishment of a disease signature by comparison of IPSC-derived neurons with established animal models of schizophrenia and Asperger autism (PCP, DISC1 deficiency, maternal immune activation) by high throughput transcriptome sequencing, proteome analysis as well as histological analyses of synapse stabilization
3. Application of known and novel drugs for schizophrenia in IPSC models in vitro and in animal disease models in vivo and in depth characterization
a) by transcriptome sequencing
b) by proteome analysis
c) by histological analysis of synapse stabilization
d) by behavioural analysis
e) by analysis of specific drug action through comparison of schizophrenia models to autism models
The novel test system as project goal aims at the preparation of potential drugs for the introduction into clinical trials.
- CeGaT Center for Genomics and Transcriptiomics GmbH Tübingen
- Pharmaseed Ltd, Ness-Ziona, Israel
- Sylics, Amsterdam, Niederlande
- Universität Tübignen, Abteilung Psychatrie