Knowing how tissue interactions affect physiology is important for understanding pathologies of hormonally regulated organs. In the uterus, tissue interactions mediate steroid hormone effects, playing key roles in events of early pregnancy. Although estrogen regulates cell signaling in a stroma-to-epithelium direction in the uterus, a paracrine factor mediating this effect has not been identified. Also, hormonal regulation of a pathway in the reciprocal direction has not been studied. In both human and rodent, estrogen stimulation of a progesterone dominated uterus causes proliferation of the endometrial stroma. Proposed studies will test the hypothesis: 1) Progesterone priming for and estrogen induction of cellular proliferation in the uterine stroma occurs indirectly through activation of progesterone receptor (PR) and estrogen receptor-alpha (ER alpha) in the overlying epithelium. 2) IGF-I is a paracrine mediator of steroid action in the uterus. The hypothesis will be tested using tissue recombinations grown in xenograft. Uterine epithelium (epi) and mesenchyme (mes) will be derived from neonatal wild-type mice, ER alpha knockout (ER alpha KO) mice, PR knockout (PRKO) mice, or IGF-I knockout mice. These knockout models were chosen because: ER alpha KO mouse uterus shows no growth response to estradiol stimulation, indicating that it is devoid of any growth-promoting ER; PRKO mouse uterus exhibits no stromal response to progesterone/estrogen treatment or to a decidualizing stimulus; in the IGF-I knockout mouse uterus estrogen stimulated cells are arrested in G2.
The specific aims are: 1. Determine the tissue specificity of the steroid receptor-mediated events regulating cell proliferation. 2. Determine the role of tissue specific expression of IGF-I in mediation of steroid induced proliferation in the uterus. For each type of knockout animal, tissue will be separated and recombined in all 4 possible combinations: epi+/mes+, epi-/mes-, epi+/mes-, epi-/mes+ (+, target gene status). Tissue recombinants will be grown in athymic mice. Effects of hormone treatments will be tested using tritiated thymidine incorporation or mitotic index as the endpoint. If hypothesis 1 proves correct, this will be a novel demonstration of hormonal regulation via an epithelium-to-stroma interaction, thereby leading to a new concept of hormone action in steroid-responsive organs. If IGF-I proves critical for tissue interactions it will be the first paracrine factor to be definitively identified as a mediator of steroid action in the uterus.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD037025-01A2
Application #
6128853
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Yoshinaga, Koji
Project Start
2000-04-15
Project End
2005-03-31
Budget Start
2000-04-15
Budget End
2001-03-31
Support Year
1
Fiscal Year
2000
Total Cost
$226,141
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Tan, Bailin; Long, Xinghua; Nakshatri, Harikrishna et al. (2008) Striatin-3 gamma inhibits estrogen receptor activity by recruiting a protein phosphatase. J Mol Endocrinol 40:199-210
Dynlacht, Joseph R; Tyree, Craig; Valluri, Shailaja et al. (2006) Effect of estrogen on radiation-induced cataractogenesis. Radiat Res 165:9-15
Bigsby, Robert M; Caperell-Grant, Andrea; Berry, Nicholas et al. (2004) Estrogen induces a systemic growth factor through an estrogen receptor-alpha-dependent mechanism. Biol Reprod 70:178-83
Mazdai, Anita; Dodder, Nathan G; Abernathy, Mary Pell et al. (2003) Polybrominated diphenyl ethers in maternal and fetal blood samples. Environ Health Perspect 111:1249-52
Fan, Meiyun; Bigsby, Robert M; Nephew, Kenneth P (2003) The NEDD8 pathway is required for proteasome-mediated degradation of human estrogen receptor (ER)-alpha and essential for the antiproliferative activity of ICI 182,780 in ERalpha-positive breast cancer cells. Mol Endocrinol 17:356-65
Fan, Meiyun; Long, Xinghua; Bailey, Jason A et al. (2002) The activating enzyme of NEDD8 inhibits steroid receptor function. Mol Endocrinol 16:315-30
Long, X; Gize, E A; Nephew, K et al. (2001) Evidence for estrogenic contamination of the MAPK inhibitor PD98059. Endocrinology 142:5390-3
Long, X; Burke, K A; Bigsby, R M et al. (2001) Effects of the xenoestrogen bisphenol A on expression of vascular endothelial growth factor (VEGF) in the rat. Exp Biol Med (Maywood) 226:477-83