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

项目 1 - 雌激素和孕激素对人类子宫内膜细胞增殖的调节

基本信息

批准号：
8069221
负责人：
JEFFREY W. POLLARD
金额：
$ 53.71万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8069221
关键词：
1-Phosphatidylinositol 3-Kinase Age Animals Biopsy Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Nucleus Cell Proliferation Cell division Cells Chromatin Chromosomes Clinical Complex Consultations Contraceptive methods Cyclin D1 Cyclin-Dependent Kinase 4 Cyclins DNA biosynthesis Data Differentiation and Growth Disease Endometrial Endometrial Carcinoma Endometrium Epithelial Epithelial Cell Proliferation Epithelial Cells Epithelium Estradiol Estrogens Event Female Fertility Glycogen Synthase Kinases Gonadal Steroid Hormones Growth Factor Hormones Human Hyperplasia Immunodeficient Mouse Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Kidney Knockout Mice Life Maintenance Malignant Neoplasms Menopause Modeling Molecular Morbidity - disease rate Mus Nuclear Pathway interactions Phase Phosphorylation Premalignant Prevention Production Progesterone Progesterone Receptors Proteins Proto-Oncogene Proteins c-akt Raloxifene Recombinants Regulation Regulatory Pathway Replication Licensing Retinoblastoma Protein Risk Role Selective Estrogen Receptor Modulators Signal Transduction Signal Transduction Pathway Site Tamoxifen Testing Time Translations Transplantation Uterine hemorrhage Uterus Woman Xenograft Model Xenograft procedure asoprisnil base capsule cell type endometriosis high risk hormone regulation hormone therapy human morbidity human tissue inhibitor/antagonist insight mortality receptor research study response sperm cell translational approach volunteer

项目摘要

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.

子宫内膜增生性疾病是常见的，估计有50%的妇女寻求