PROJECT 1 - Estrogen and Progesterone Regulation of Uterine Cell Proliferation

项目 1 - 雌激素和孕激素对子宫细胞增殖的调节

• 批准号: 8449981
• 负责人: JEFFREY W. POLLARD
• 金额: $ 53.64万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449981
• 关键词: 1-Phosphatidylinositol 3-Kinase; Age; Animals; Biopsy; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Nucleus; Cell Proliferation; Cell division; 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; Estradiol Receptors; Estrogens; Event; Female; Fertility; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Gonadal Steroid Hormones; Growth Factor; Hormones; Human; Hyperplasia; Immunodeficient Mouse; Insulin-Like Growth Factor I; Kidney; Knockout Mice; MCM Protein; Maintenance; Malignant Neoplasms; Menopause; Modeling; Molecular; Morbidity - disease rate; Mus; Nuclear; Pathway interactions; Phosphorylation; Premalignant; Prevention; Production; Progesterone; Progesterone Receptors; Proto-Oncogene Proteins c-akt; Raloxifene; Recombinants; Regulation; Regulatory Pathway; Replication Licensing; Reproductive Biology; Retinoblastoma Protein; Risk; Role; S Phase; Selective Estrogen Receptor Modulators; Signal Transduction; Signal Transduction Pathway; Site; Tamoxifen; Testing; Time; Translations; Transplantation; Uterine hemorrhage; Uterus; Woman; Women' s Health; Xenograft Model; Xenograft procedure; asoprisnil; base; capsule; cell type; endometriosis; high risk; hormone regulation; hormone therapy; human morbidity; human mortality; human tissue; inhibitor/antagonist; insight; mortality; receptor; research study; response; translational approach; volunteer

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很常见，估计有50%的女性寻求 在她们生命中的某个时刻，咨询异常子宫出血。随着女性年龄的增长， 子宫内膜疾病随着未治疗的子宫内膜疾病的增加而增加， 子宫内膜癌，其中在美国每年有大约40，000个新病例。但尽管 发病率高，死亡率高，人子宫内膜细胞的分子调控 对扩散的了解很少。在人和小鼠子宫内膜中，雌二醇-17（E2）刺激 上皮细胞增殖，而孕酮（P4）抑制它。在小鼠中，我们以前的研究 明确了Ej刺激和P4抑制的两条信号转导通路，这两条通路是Ej诱导细胞凋亡所必需的 子宫上皮细胞增生。它们是：1）通过IGF-1调节pRb磷酸化 信号传导和2）通过控制DNA复制许可。利用这些在小鼠子宫中的研究， 作为指导，我们计划利用直接翻译的方法来阐明人类子宫内膜异位症的分子基础。 上皮细胞增殖具体目标是： 1.表征典型细胞周期的调控和DNA复制许可的调控 女性性类固醇激素在人类子宫上皮中的作用途径。 2.利用小鼠xe nog筏模型研究人子宫内膜增殖的调控; 先前获得的关于小鼠子宫内膜调节的数据作为指导。 3.阐明选择性调节雌二醇和孕酮激活的细胞周期途径 异种移植的人子宫内膜中的受体。 这些研究将为E2和P4的作用机制提供独特的见解， 治疗上有价值的SERMs和SPERM。这些数据可以应用于广泛的临床情况 来改善人类的发病率和死亡率。这些措施包括预防子宫增生和癌症， 高风险情况下，在需要时促进最佳增长和差异化，例如 生育力和抑制分化时，它是不需要的，例如，避孕和绝经 荷尔蒙疗法