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Title: Transcriptional regulation of the mineralocorticoid receptor in response to cellular injury
Author: Kang, Peng
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2009
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This study has aimed to increase our knowledge of the mechanisms underlying the transcriptional regulation of MR. The rat MR gene gives rise, through alternative splicing, to three distinct MR mRNA transcripts (MRα, β and γ). Transcription of each MR variant was measured in various in vitro models of cell injury at both the promoter and mRNA level. The results suggest that MRα and MRβ variants are responsive to some but not all types of cell injury while MRγ appears to be unaffected under any condition. These effects are more prominent in cells with a neuronal-like phenotype. Increased MR expression is not a generic response to injury. Preliminary data suggest that the main regulatory elements in the MRα promoter occurs in a region ~ 1.5Kb from the translation start site whereas for the MRβ promoter the crucial regulatory region is within the first 300bp. The abundance of each brain MR variant was also measured in an in vivo injury model of hypothermic anoxic injury in neonatal rats where damage occurs predominantly in the hippocampus – the region with the highest expression of MR. Levels of MRβ mRNA were significantly increased in all regions of the hippocampus under hypothermic conditions and further increased in the presence of anoxia. Unexpectedly, hypothermia also induced MRγ expression in select hippocampal sub-regions while MRα was without effect. These observations corroborate the in vitro data in demonstrating a key role for the MRβ variant in response to ischaemic injury and support the hypothesis that some of neuroprotective effects of hypothermia are mediated via MR. The results should contribute to the future clinical exploitation of the protective effects of MR in patients at high risk of cerebral ischaemia.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available