Progesterone Action in the Uterus of Mice and Humans

描述（由申请人提供）：子宫内膜增生性疾病很常见，估计有50%的妇女在其生命的某个阶段因异常子宫出血而寻求咨询。随着女性年龄的增长，子宫内膜癌前病变的风险增加，未接受治疗的女性患子宫内膜癌的风险增加，其中美国每年约有40，000例新发病例。此外，子宫内膜异位症是一种子宫内膜增生性疾病，影响6-10%的妇女，35%的妇女伴有疼痛或不孕症。然而，尽管有大量的发病率和显著的死亡率，人类子宫内膜细胞增殖的分子控制知之甚少。在人类和小鼠子宫内膜中，雌二醇-172（E2）刺激上皮细胞增殖，而孕酮（P4）抑制上皮细胞增殖。在小鼠中，我们的研究已经确定了E2诱导子宫上皮细胞增殖所需的两条信号转导途径，即E2刺激和P4抑制。这些措施是：1）E2通过IGF-1 R诱导信号传导，其刺激PI 3-激酶途径以最终抑制GSK-32，从而导致CyclinD 1/CDK 4活性激酶复合物的核定位和pRb磷酸化。2)通过调控DNA合成起始所需的微染色体维持蛋白来控制DNA复制许可。以小鼠子宫的这些研究为指导，我们计划利用直接翻译的方法来阐明人类子宫上皮细胞增殖的分子基础。这些研究将使用来自育龄中期妇女的子宫内膜活检和一种新的异种移植模型来研究人类子宫内膜功能。具体目标是：1）表征女性性类固醇激素在人子宫上皮中对典型细胞周期和DNA复制许可调节途径的调节。2)利用小鼠异种移植模型研究人子宫内膜增殖的调控。3)阐明异种移植人子宫内膜中雌激素和孕激素受体选择性调节激活的细胞周期途径。这些研究将为E2和P4的作用机制以及具有治疗价值的SERM和SPRMS提供独特的见解。这些数据可以应用于广泛的临床情况，以改善人类的发病率和死亡率。这些措施包括预防高风险情况下的子宫增生和癌症以及子宫内膜异位症，在需要时促进最佳生长和分化，例如生育，并在不需要时抑制分化，例如避孕和更年期激素治疗。公共卫生相关性：这些研究将为E2和P4的作用机制以及具有治疗价值的SERM和SPERM提供独特的见解。这些数据可以应用于广泛的临床情况，以改善人类的发病率和死亡率。这些措施包括预防高风险情况下的子宫增生和癌症以及子宫内膜异位症，在需要时促进最佳生长和分化，例如生育，并在不需要时抑制分化，例如避孕和更年期激素治疗。

DESCRIPTION (provided by applicant): 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 pre-malignant 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. Furthermore endometriosis a proliferative disease of the endometrium, affects 6-10% of women and 35% with pain or infertility. However, despite this 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-172 (E2) stimulates epithelial cell proliferation whilst progesterone (P4) inhibits it. In both cases initial signaling is through their respective receptors (ER and PR). In the mouse, our studies have defined two signal transduction pathways stimulated by E2 and inhibited by P4 required for E2 induced uterine epithelial cell proliferation. These are: 1) E2 induced signaling through IGF-1R that stimulates the PI3-kinase pathway to ultimately inhibit GSK-32 with the resultant nuclear localization of CyclinD1/CDK4 active kinase complexes and pRb phosphorylation. 2) Through the control of DNA replication licensing by regulation of Minichromosome Maintenance Proteins that are required for DNA synthesis initiation. 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. These studies will use endometrial biopsies form mid-reproductive age women and a novel xenotransplantation model for studying human endometrial function. 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 xenograft model to study the regulation of human endometrial proliferation. 3) Elucidate the cell cycle pathways activated by selective modulation of estrogen and progesterone receptors in xenotransplanted human endometrium. These studies will provide unique insights in humans into the mechanism of action of E2 and P4 as well as for the therapeutically valuable SERMs and SPRMSs. 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 and endometriosis, 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. PUBLIC HEALTH RELEVANCE: These studies will provide unique insights in humans 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 and endometriosis, 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.