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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD058155-05
Application #
8449981
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$519,795
Indirect Cost
$219,690
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Kuokkanen, Satu; Polotsky, Alex J; Chosich, Justin et al. (2016) Corpus luteum as a novel target of weight changes that contribute to impaired female reproductive physiology and function. Syst Biol Reprod Med 62:227-42
Al-Safi, Zain A; Liu, Huayu; Carlson, Nichole E et al. (2016) Omega-3 Fatty Acid Supplementation Lowers Serum FSH in Normal Weight But Not Obese Women. J Clin Endocrinol Metab 101:324-33
Wooding, Kerry M; Hankin, Joseph A; Johnson, Chris A et al. (2015) Measurement of estradiol, estrone, and testosterone in postmenopausal human serum by isotope dilution liquid chromatography tandem mass spectrometry without derivatization. Steroids 96:89-94
Wang, Yuxiang; Zhu, Liyin; Kuokkanen, Satu et al. (2015) Activation of protein synthesis in mouse uterine epithelial cells by estradiol-17β is mediated by a PKC-ERK1/2-mTOR signaling pathway. Proc Natl Acad Sci U S A 112:E1382-91
Merhi, Zaher; Polotsky, Alex J; Bradford, Andrew P et al. (2015) Adiposity Alters Genes Important in Inflammation and Cell Cycle Division in Human Cumulus Granulosa Cell. Reprod Sci 22:1220-8
Roth, Lauren W; Allshouse, Amanda A; Bradshaw-Pierce, Erica L et al. (2014) Luteal phase dynamics of follicle-stimulating and luteinizing hormones in obese and normal weight women. Clin Endocrinol (Oxf) 81:418-25
Neal-Perry, Genevieve; Yao, Dachun; Shu, Jun et al. (2014) Insulin-like growth factor-I regulates LH release by modulation of kisspeptin and NMDA-mediated neurotransmission in young and middle-aged female rats. Endocrinology 155:1827-37
Ross, Lauren A; Polotsky, Alex J; Kucherov, Alexander et al. (2014) Profound reduction of ovarian estrogen by aromatase inhibition in obese women. Obesity (Silver Spring) 22:1464-9
Roth, Lauren W; Bradshaw-Pierce, Erica L; Allshouse, Amanda A et al. (2014) Evidence of GnRH antagonist escape in obese women. J Clin Endocrinol Metab 99:E871-5
Meek, Thomas H; Matsen, Miles E; Damian, Vincent et al. (2014) Role of melanocortin signaling in neuroendocrine and metabolic actions of leptin in male rats with uncontrolled diabetes. Endocrinology 155:4157-67

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