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Title: Biomarker identification in post-mortem brain tissue and pre-clinical models of schizophrenia
Author: Chan, M. K.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2010
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In this thesis, a reproducible proteomic profiling workflow was established for investigating brain tissue subproteomes. Parallel proteomic and metabonomic studies were then conducted to: 1) investigate the effects of lifetime medication in the prefrontal cortex of schizophrenia patients as a means to identify ‘disease signatures’ and targets of ‘drug effects’ and to examine specificity of the changes relative to bipolar disorder; 2) evaluate the effects of sub-chronic antipsychotic drug treatment in rats as a validation tool to confirm patient data and further elucidate the molecular mechanisms of these drugs; and 3) examine the effects of acute and chronic PCP treatments in rats to address their level of molecular similarity with the pathology of schizophrenia. Novel protein and metabolite ‘disease signatures’ were identified in the prefrontal cortex of schizophrenia patients. Medication was found to exert neuroadaptive effects on schizophrenia signatures. Drug effects on these signatures were confirmed in animal models of antipsychotic drugs. Novel functional processes affected by drugs were also discovered. Different panels of ‘disease signatures’ were identified for schizophrenia and bipolar disorder indicating specificity of the changes and diverging pathogenesis. Molecular similarities and differences were identified between the two PCP models (acute and chronic) and schizophrenia patients. This thesis successfully demonstrates the utility of subproteome and metabonome profiling approaches for providing new insights into fundamental questions of the pathophysiology and therapeutics of schizophrenia. The knowledge obtained provides a platform for subsequent hypothesis-driven functional investigations, generation of new hypotheses and drug discovery strategies which currently remain dominated by the redesign of drugs for familiar targets.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available