TYPE II 3BETA HSD GENE REGULATION OF DHEAS SYNTHESIS

Project: Research project

Project Details

Description

Dehydroepiandrosterone and its sulfate (DHEA(S)) show a cycle of large
changes in secretion from the adrenal cortex over the life span in humans.
The secretion of these steroids is very high in the fetus, low in
childhood, high again in young adulthood, followed by a progressive age-
related decline. Dependent on age, 40-100% of local tissue androgens and
estrogens in both men and women are derived from DHEAS. The critical regulatory point in the biosynthesis of DHEAS is 3beta-
hydroxysteroid/delta4 '5-isomerase (3beta-HSD). The low level of activity
of this enzyme in the human adrenal cortex, but not in animal glands such
as that of the cow, limits the flux of pregnenolone to A steroids, such as
cortisol, and maintains the synthesis of delta5 steroids, principally
DHEA(S). The proposed experiments will analyze the differences between the
type Il human 3beta-HSD gene, which is expressed in the adrenal cortex and
other steroidogenic tissues, and the 3beta-HSD gene expressed in the bovine
adrenal. Transcription rates and mRNA stability will be assessed as possible causes
of the differences in 3beta-HSD expression between the bovine and human
adrenal cortex, and between the different zones of the human adrenal
cortex. The bovine 3beta-HSD gene (or genes) expressed in the adrenal
cortex will be isolated, its structure analyzed, and the tissue
distribution of its transcript determined. The difference in expression
levels between the human type Il and the bovine gene will be tested using
reporter constructs from the two genes transfected into primary human and
bovine adrenal cells. The elements in the type II human and the bovine
3beta-HSD genes responsible for tissue-specific expression and second
messenger regulation, and nuclear proteins from the adrenal cortex that
bind to these elements, will be characterized. The possible identity of
such proteins to known transcription factors will be tested. Cell culture
experiments will examine whether the cycle of DHEAS synthesis over the life
span in humans results from intrinsic changes in expression of 3beta-HSD.
The abundance in adrenocortical tissue of nuclear proteins that bind to the
regulatory elements of the type II 3beta-HSD gene will be correlated with
the cycle. These experiments will elucidate the molecular basis for the regulation of
the human 3beta-HSD type
II gene and thereby the regulation of DHEAS synthesis. This information
will provide a basis for understanding the significance of the unique
secretion of this hormone in humans and the significance of its age-related
decline for aging and age-related diseases.
StatusFinished
Effective start/end date9/30/948/31/09

Funding

  • National Institutes of Health: $340,284.00
  • National Institutes of Health: $5,000.00
  • National Institutes of Health
  • National Institutes of Health: $278,795.00
  • National Institutes of Health
  • National Institutes of Health: $5,000.00
  • National Institutes of Health
  • National Institutes of Health: $164,730.00
  • National Institutes of Health
  • National Institutes of Health: $5,000.00
  • National Institutes of Health: $328,423.00
  • National Institutes of Health: $271,310.00
  • National Institutes of Health: $338,275.00
  • National Institutes of Health: $5,000.00
  • National Institutes of Health: $5,000.00
  • National Institutes of Health: $318,861.00
  • National Institutes of Health: $152,299.00
  • National Institutes of Health: $340,237.00
  • National Institutes of Health: $270,439.00
  • National Institutes of Health: $5,000.00

ASJC

  • Medicine(all)

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