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Title: Regulation of II-beta-hydroxysteroid dehydrogenase in rat brain and cloning of the gene promoter region
Author: Marie-Pierre, M.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1993
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Adrenal corticosteroid hormones play a diverse and important role in development and homeostasis. Their complex effects are predominantly mediated by intracellular receptors, which are of two types; mineralocorticoid (MR, type I) and glucocorticoid (GR, type II). MR bind aldosterone and physiological glucocorticoids (cortisol, corticosterone) with equivalent high affinity in vitro, whereas GR show a low affinity for aldosterone but bind physiological glucocorticoids and the synthetic glucocorticoid dexamethasone with high affinity. In vivo, kidney MR selectively bind aldosterone despite a hundred-fold molar excess of circulating glucocorticoids. This selectivity is due to the high activity of the enzyme 11β-hydroxysteroid dehydrogenase (11β-OHSD) which catalyses the reversible conversion of physiological glucocorticoids to inactive products, but does not metabolise aldosterone, thus preventing glucocorticoid access to renal MR. This thesis describes firstly the presence and subregional distribution of 11β-OHSD in rat brain using Northern analysis, in situ hybridisation, and an 11β-OHSD activity assay. The enzyme was not only found in aldosterone selective regions, such as periventricular areas of the hypothalamus, but also in hippocampus where corticosterone is the physiological ligand for MR, and, more surprisingly, in cerebellum which contains very low levels of MR. Therefore it was postulated that 11β-OHSD might modulate glucocorticoid access to both types of corticosteroid receptor in brain. Furthermore, brain but not renal, 11β-OHSD was up-regulated by chronic glucocorticoid but not aldosterone administration, suggesting a role for the enzyme in controlling long-term neuronal glucocorticoid exposure. The importance of 11β-OHSD in brain was further substantiated by the finding of high 11β-OHSD mRNA levels and activity in rat brain subregions in the early postnatal period, with regionally specific developmental patterns of activity. The enzyme may play an important role in the developing brain by protecting tissues from (or exposing them to) elevated corticosterone levels. To understand the molecular mechanisms underlying tissue-specific and ontogenic regulation of 11β-OHSD a rat genomic clone was isolated and partially sequenced. Differential promoter usage of the gene was demonstrated in kidney; three transcription start sites were detected within one kilobase of 5' flanking region of the gene, using primer extension and ribonuclease protection analysis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available