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dc.contributor.advisorHardingham, Giles
dc.contributor.advisorMcColl, Barry
dc.contributor.advisorDrake, Mandy
dc.contributor.advisorSalman, Rustam Al-Shahi
dc.contributor.authorLoan, James J.M.
dc.date.accessioned2022-06-22T08:55:14Z
dc.date.available2022-06-22T08:55:14Z
dc.date.issued2022-06-16
dc.identifier.urihttps://hdl.handle.net/1842/39165
dc.identifier.urihttp://dx.doi.org/10.7488/era/2416
dc.description.abstractSpontaneous intracerebral haemorrhage (ICH) is associated with substantial morbidity and mortality. Randomised trials of treatments to reduce haematoma volumes have not demonstrated efficacy. Nrf2 is a transcription factor that responds to oxidative stress by inducing antioxidant gene expression. Perihaematomal oedema (PHO) after ICH may reflect modifiable processes of inflammation and secondary injury. In a prospective, community-based ICH inception cohort, I found that early PHO was not associated with death or dependency, independent of haematoma volume. Because later PHO has been associated with poor outcome, this indicates a window where the link between oedema and outcome is not yet established. After systematically identifying all published studies of molecular measures of inflammation in patient brain tissue after ICH, I performed a meta-analysis which established that the proinflammatory cytokine interleukin-1β is increased within 6h of ICH onset. However, meta-analysis of other measures of inflammation was not possible because of limited replication and poor reporting. I therefore compared brain transcriptomes from patients who died after ICH with those who died suddenly of non-neurological disease using bulk RNA sequencing and dual in situ RNA hybridisation-immunohistochemistry (IHC). Genes which are specifically expressed by myeloid cells or astrocytes were increased after ICH and coexpressed with Nrf2 target genes. I modelled ICH in mice using striatal bacterial collagenase injection and conditionally deleted myelomononuclear Nrf2 using cre-mediated excision. I used grip strength assessment, IHC and bulk RNA sequencing of sorted myelomononuclear cells and found that myelomononuclear Nrf2 is protective and facilitates cell autonomous adaptive responses to ICH whilst suppressing interferon stimulated gene expression. In co-cultured primary microglia, astrocytes, and neurons, I confirmed that microglial Nrf2 activation facilitates adaptive microglial transcriptional responses to blood clot conditioned media and blunts lipopolysaccharide-induced astrocytosis. Myelomononuclear Nrf2 is therefore a tractable therapeutic target for ICH. Future work should dissect specific roles and protective mechanisms of downstream Nrf2-regulated responses to ICH.en
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.titleModulation of inflammation after brain haemorrhage by myelomononuclear Nrf2en
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2023-06-16en
dcterms.accessRightsRestricted Accessen


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