Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.666132
Title: Transcriptional regulation of the rat glucocorticoid receptor gene
Author: McCormick, J. A.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2000
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Abstract:
The aims of this thesis were to investigate tissue-specific regulation of the rat GR gene and how this relates to perinatal programming of GR levels. RNase protection analysis was used to determine the relative tissue distributions of alternate exon 1-contianing GR mRNAs. One alternate exon 1, exon 110, was found to be present in the majority (56-87%) of GR mRNAs in a variety of tissues, including hippocampus, liver and thymus. Mapping of the 5' end of exon 110 revealed substantial heterogeneity in transcription initiation points. Other alternate exons 1 exhibited tissue-specific distributions. For example, exon 11-containing GR mRNAs were restricted to thymus, while exon 17-containing GR mRNAs are hippocampus-specific. To address the mechanisms of perinatal programming of GR levels, RNase protection analysis was used to assess changes in the abundances of alternate GR mRNAs in the liver of adult rats exposed to dexamethasone in utero. A significant reduction (13%, p<0.05) in the proportion of exon 110-containing GR was detected, suggesting an increase in the proportion of a minor GR mRNA variant. Further experiments, however, did not identify a variant GR mRNA upregulated by this manipulation. 5'-Rapid amplification of cDNA ends PCR performed on primary hippocampal cultures revealed that the majority of GR mRNAs expressed by these cultures contain exon 110 and strengthened the earlier finding that transcription initiation of this variant transcript exhibits considerable heterogeneity. RT-PCR performed on these culture revealed that primary hippocampal culture express GR mRNAs containing exon 17, which is specifically induced in the hippocampus by neonatal handling, suggesting that these cultures might provide a useful system to elucidate the mechanisms by which neonatal handling leads to permanently increased hippocampal GR. An understanding of the molecular mechanisms underlying programming of GR is of great importance in gaining an understanding of how tissue-specific regulation of GR occurs and how early life events influence adult disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.666132  DOI: Not available
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