ACTIONS OF ESTROGEN IN MATURING GRAAFIAN FOLLICLES

  • Veldhuis, Johannes D (PI)

Project: Research project

Project Details

Description

Normal ovarian follicular development culminates in a biosynthetically
competent corpus luteum, which is essential for normal reproductive
function in the female. Extensive experimental work in various mammalian
species has demonstrated significant endocrine regulation of certain key
steps in gonadal steroidogenesis and intracellular sterol metabolism. We
have used a well-defined monolayer cell culture system consisting of
hormonally responsive untransformed swine ovarian (granulosa) cells to
examine the specific enzymes by which estradiol, FSH, and IGF-I act singly
and in combination to regulate specific sterol-metabolizing enzymes under
experimentally controlled conditions in vitro. Among the major regulated
sites we have studied, and propose to study further are: (i) the LDL
receptor; (ii) the cholesterol side-chain cleavage enzyme; (iii) the HMG
CoA reductase enzyme; and (iv) the sterol-carrier protein (SCP-2). To
date, most of our and other studies have evaluated hormonal regulation of
sterol processing at the level of LDL receptor number, enzyme biochemical
activity and/or the amount of specific protein synthesized. Our renewal
proposal continues logically from these earlier investigations by focusing
on the specific hormonal regulation of genomic expression. This emphasis
is strongly supported by methods and progress achieved under my parallel
RCDA, for example in which we have been able to demonstrate prominent (3-10
fold) stimulation of specific CSCC mRNA accumulation not only by FSH or
IGF-I acting alone, but also by estradiol FSH and IGF-I acting
synergistically. In contrast, gene expression of a constitutively active
enzyme, phosphoglyceraldehyde dehydrogenase, is not induced by these
hormones. Accordingly, we are now in an excellent position to use this
primary granulosa-cell culture system further to examine the coordinate
regulation of gonadal-cell sterol metabolism at the mRNA level. Notably,
the swine granulosa cell in vitro system is almost unique in that it
manifests prominent steroidogenic responses to three major classes of
hormones acting-alone or in concert: viz., the steroid hormone, estradiol;
the gonadotropin, FSH; and the insulin-like growth factor, IGF-I. Thus,
three significant and distinct "pathways of hormone action can be in, and
jointly-in this experimental model. Our aims encompass an investigation of
steady-state mRNA concentrations, gene transcription rates, and in situ
molecular hybridization. Studies of the individual and coordinate
regulation of sterol-metabolizing enzymes and genes as proposed here should
contribute significantly to our better understanding of the essential
mechanisms by which relevant hormones act both singly and in concert to
promote the remarkable increases in steroidogenic differentiation required
during follicular maturation. The preceding studies should contribute
important new insights into and further developments in fertility
regulation in man, domestic animals, and endangered wild species.
StatusFinished
Effective start/end date2/1/836/30/07

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $147,860.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $260,100.00
  • National Institutes of Health: $260,100.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $260,100.00
  • National Institutes of Health: $260,100.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $217,525.00
  • National Institutes of Health
  • National Institutes of Health: $221,976.00

ASJC

  • Medicine(all)

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