PROJECT 1 - Estrogen and Progesterone Regulation of Uterine Cell Proliferation

子宫内膜增生性疾病很常见，估计有50%的女性寻求 在他们生命中的某个时候咨询异常子宫出血。随着女性年龄的增长，癌前病变的风险 未接受治疗的患者子宫内膜紊乱程度增加，患病风险增加。 子宫内膜癌，在美国每年大约有40,000个新病例。然而，尽管 人子宫内膜细胞的大量发病率和显著死亡率、分子调控 人们对核扩散知之甚少。雌二醇-17(3(E_2))对人和小鼠子宫内膜的刺激作用 上皮细胞增殖，而孕酮(P4)抑制它。在小鼠身上，我们之前的研究已经 确定了EJ诱导所需的两条信号转导通路，分别受EJ刺激和P4抑制 子宫上皮细胞增殖。它们是：1)通过IGF-1调节pRb的磷酸化 2)通过DNA复制许可的控制。利用这些在小鼠子宫中的研究作为 作为指南，我们计划利用直接翻译的方法来阐明人类子宫的分子基础。 上皮细胞增殖。具体目标是： 1.描述规范细胞周期的调控和DNA复制许可调控 女性性类固醇激素在人子宫上皮细胞中的作用途径。 2.利用小鼠Xe-nog移植模型研究人子宫内膜增殖的调控； 以前获得的关于小鼠子宫内膜调控的数据作为指导。 3.阐明雌二醇和孕酮选择性调节激活的细胞周期通路 异种移植子宫内膜中的受体。 这些研究将对E2和P4的作用机制以及对 具有治疗价值的SERM和精子。这样的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。这些措施包括预防子宫增生和癌症。 高风险情况，在需要时促进最佳增长和差异化，例如在 生育和在不需要时抑制分化，例如避孕和更年期 激素疗法。

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.