17 alpha-Hydroxylase Expression in Human Ovarian Cells

Project: Research project

Project Details

Description

The proposed experiments are designed to elucidate the regulatory mechanisms underlying androgen
biosynthesis in theca interna cells from ovaries of normal cycling women and women with polycystic ovary
syndrome (PCOS). During the past funding period, we obtained exciting data demonstrating that increased
androgen production and augmented P450 17a-hydroxylase (CYP17) gene expression in PCOS theca cells
results from a combined reduction in the activation state of the MEK1/ERK pathway and a stimulation in the
activation state of the MKK3 pathway. We have observed that infection of normal theca cells with
adenovirus expressing dominant negative MEK1 and constitutively active MKK3 recapitulates a PCOS theca
cell phenotype. We now have the tools to fully explore the contributions of the other components of the
MAPK signaling pathways. In this proposal we will test the hypothesis that increased ovarian androgen
production is a consequence of altered mitogen activated protein kinase (MAPK) signaling in PCOS theca
cells. Aim 1 studies are designed to investigate whether dysregulation of upstream signaling component(s)
of the ERK and p38 signaling pathway(s) (i.e., Raf-1, MEKK1, MEKK3) directly affect the down stream
signaling components of each homologous pathway to the extent that CYP17 and CYP11A1 gene
expression, and androgen biosynthesis are up-regulated in PCOS theca cells. We will also examine whether
dysregulation of signaling components from one pathway result(s) in compensatory changes in signaling
through parallel pathway(s). In Aim 2 we will investigate the extent to which alterations in ERK and p38
signaling contribute to increased CYP17 and CYP11A1 gene transcription and mRNA stability in PCOS
theca cells.
Throughout the literature there are data to support that tumor necrosis factor a (TNF) inhibitsthecal
CYP17 gene expression and androgen biosynthesis. However, these data are contradictory with the
observation that PCOS women have elevated circulating plasma and follicular fluid levels of TNF. In Aim 3,
we will examine the extent to which defects in MAPK signaling in PCOS theca cells affects TNF-dependent
regulation of androgen biosynthesis. Results of these studies will provide both new insights regarding the
cause and molecular basis for increased ovarian androgen production, and lead to the development of new
targets for treatment of women with PCOS.
StatusFinished
Effective start/end date9/30/962/28/13

Funding

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $241,507.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $241,481.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $289,269.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $237,629.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $241,533.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $265,654.00

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