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dc.contributor.authorvan Rees, Geertje Frederique
dc.date.accessioned2018-06-08T10:25:13Z
dc.date.available2018-06-08T10:25:13Z
dc.date.issued2018-07-20
dc.date.submitted2017-11-28
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/276763
dc.description.abstractAbnormal activation of brain microglial cells is widely implicated in the pathogenesis of schizophrenia. The disrupted balance of microglia phenotypes has been hypothesized to influence the clinical course of the disease and affect symptom severity. Previously, the pathophysiology of microglial activation was considered to be intrinsic to the central nervous system. We hypothesised that due to their perivascular localization, microglia can also be activated by factors present in circulating blood. We applied a high-content functional screening platform, to characterize alterations in microglial intracellular signalling cascades induced by schizophrenia patient serum relative to control serum. Using automated sample preparation, fluorescent cellular barcoding and flow cytometry, the applied platform is capable of detecting multiple parallel cell signalling responses in microglia. First, we exposed a human microglia cell line to serum isolated from first-onset drug-naïve schizophrenia patients (n=60) and healthy controls (n=79). We were able to show that peripheral blood serum obtained from schizophrenia patients induced differential microglial cell signalling network responses in vitro. We subsequently assessed whether antipsychotic drug-treatment can normalise the abnormal microglial signalling responses previously identified by exposing microglia cells to serum from antipsychotic treated schizophrenia patients (n=15) and controls (n=17). In addition, in order to assess microglia activation in vivo, we obtained positron emission tomography (PET) imaging data from collaborators, who used a radiotracer to assess potential altered microglia activation in patients suffering from schizophrenia. Finally, as a proof of concept study, we attempted to validate these findings by assessing the effect of serum collected from first-onset drug-naïve schizophrenia patients (n=9), controls (n=12) as well as serum isolated from the same patients subjected to six weeks of clinical treatment with the antipsychotic olanzapine (n=9). This study aimed to identify normalisation of previously detected differences in microglia signalling pathways based on successful in vivo treatment. We demonstrate that peripheral blood serum isolated from schizophrenia patients, independent of their treatment status, is sufficient to trigger microglial cell signalling network responses in vitro, which are indicative of altered STAT3 signalling. We further explored the composition of the serum for differential expression of analytes, previously associated with neuropsychiatric disorders, and the utility of the detected microglial cellular phenotype as a target for novel drug discovery.
dc.description.sponsorshipThis work was supported by grants from the Stanley Medical Research Institute (SMRI); the Engineering and Physical Sciences Research Council UK (EPSRC); the Dutch Government-funded Virgo consortium (ref. FES0908); the Netherlands Genomics Initiative (ref. 050-060-452) and the European Union FP7 funding scheme: Marie Curie Actions Industry Academia Partnerships and Pathways (ref. 286334, PSYCH-AID project).
dc.language.isoen
dc.rightsAll rights reserved
dc.rightsAll Rights Reserveden
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved/en
dc.subjectmicroglia
dc.subjectschizophrenia
dc.subjectpsychiatric disorder
dc.subjectmTOR
dc.subjectSTAT3
dc.subjectdrug target
dc.subjectphosphoflow
dc.subjectinflammation
dc.subjectflow cytometry
dc.subjectfluorescent barcode
dc.titleThe involvement of microglial activation in schizophrenia
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridge
dc.publisher.departmentChemical Engineering and Biotechnology
dc.date.updated2018-06-08T08:52:55Z
dc.identifier.doi10.17863/CAM.24059
dc.contributor.orcidvan Rees, Geertje Frederique [0000-0002-9431-0653]
dc.publisher.collegeQueens' college
dc.type.qualificationtitlePhD in Biotechnology
cam.supervisorBahn, Sabine
cam.thesis.fundingtrue
rioxxterms.freetoread.startdate2019-06-08


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