PROJECT 1 - Estrogen and Progesterone Regulation of Human Endometrial Cell Prolif

  • Chua, Jr., Streamson C. (PI)
  • Santoro, Nanette F. (PI)
  • Pollard, Jeffrey W. (PI)
  • Etgen, Anne (PI)
  • Santoro, Nanette F. (PI)
  • Pollard, Jeffrey W. (PI)

Project: Research project

Project Details

Description

Proliferative disorders of the endometrium are common with an estimated 50% of women seeking
consultation for abnormal uterine bleeding at some point in their lives. As women age the risk of premalignant
disorders of the endometrium increases with those not being treated showing an increased risk of
endometrial cancer, of which there are approximately 40,000 new cases in the US annually. However, despite
the large amount of morbidity and significant mortality, the molecular control of human endometrial cell
proliferation is poorly understood. In both human and mouse endometrium estradiol-17(3 (E2) stimulates
epithelial cell proliferation whilst progesterone (P4) inhibits it. In the mouse, our previous studies have
defined two signal transduction pathways stimulated by Ej and inhibited by P4 that are required for Ej induced
uterine epithelial cell proliferation. These are: 1) the regulation of pRb phosphorylation through IGF-1
signaling and 2) through the control of DNA replication licensing. Using these studies in the mouse uterus as
a guide, we plan to utilize a direct translational approach to elucidate the molecular basis of human uterine
epithelial cell proliferation. The specific aims are:
1. Characterize the regulation of the canonical cell cycle and DNA replication licensing regulatory
pathways by female sex steroid hormones in human uterine epithelia.
2. Utilize a mouse xe nog raft model to study the regulation of human endometrial proliferation;using
previously acquired data on regulation of the mouse endometrium as a guide.
3. Elucidate the cell cycle pathways activated by selective modulation of estradiol and progesterone
receptors in xenotransplanted human endometrium.
These studies will provide unique insights into the mechanism of action of E2 and P4 as well as for the
therapeutically valuable SERMs and SPERMs. Such data can be,applied to a wide range of clinical situations
to ameliorate human morbidity and mortality. These include prevention of uterine hyperplasia and cancer in
high-risk situations, promotion of optimal growth and differentiation where it is required, for example in
fertility and inhibition of differentiation when it is not required, for example, contraception and menopausal
hormonal therapy.
StatusFinished
Effective start/end date4/1/093/31/10

Funding

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development

ASJC

  • Endocrine and Autonomic Systems
  • Endocrinology
  • Cellular and Molecular Neuroscience
  • Molecular Medicine
  • Obstetrics and Gynecology
  • Developmental Neuroscience
  • Physiology
  • Cell Biology
  • Toxicology
  • Endocrinology, Diabetes and Metabolism
  • Reproductive Medicine

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