Steroid Hormone Regulation of Uterine Function and Dysfunction

描述(由申请人提供)：女性生殖道疾病是一个严重的妇女健康问题。子宫内膜癌是妇科最常见的恶性肿瘤，也是女性的第四大常见癌症。此外，据估计，美国有500万女性患有子宫内膜异位症，通常与不孕不育和盆腔疼痛有关。子宫疾病的主要特征之一是类固醇激素对子宫细胞增殖和分化的控制中断。利用高密度DNA芯片分析，我们已经确定子宫中的Mig-6是SRC-1和PR的靶标。Mig-6通过完全和有条件地切除Mig-6来调节小鼠的生育能力和P4减弱E2信号的能力。Mig-6在人类子宫内膜中的表达水平和细胞特异性均依赖于月经周期。Mig-6在子宫内膜异位症和子宫内膜癌患者中的表达降低。这一建议的总体假设是Mig-6介导了P4抑制E2引起的子宫内膜细胞增殖的能力。该提案的目的将是研究Mig-6在子宫内膜功能调节中的作用。具体目的1将通过测定Mig-6在小鼠子宫中的细胞类型特异性表达和内分泌调节，以及条件切除生殖道Mig-6小鼠的表型特征，来研究Mig-6在生育和子宫生理中的作用。具体目的2将探讨Mig-6在激素调节子宫细胞增殖和基因表达中的作用。具体目标3将利用组织重组技术研究Mig-6通过组织重组技术调节子宫内膜类固醇反应的子宫内膜室。了解Mig-6在类固醇激素调节、早期妊娠、子宫增殖和子宫凋亡中的作用，将为开发不孕症、子宫内膜异位症和子宫内膜癌的诊断和治疗工具提供策略。公共卫生相关性：Mig-6在人类子宫内膜异位症和子宫内膜癌患者中的表达降低。该提案的目的将是研究Mig-6在子宫内膜功能中类固醇激素调节中的作用。了解Mig-6在类固醇激素调节、早期妊娠、子宫增殖和子宫凋亡中的作用，将为开发不孕症、子宫内膜异位症和子宫内膜癌的诊断和治疗工具提供策略。

DESCRIPTION (provided by applicant): Diseases of the female reproductive tract represent a significant women's health problem. Endometrial cancer is the most common gynecologic malignancy and the fourth most common cancer in women. Additionally, endometriosis affects an estimated 5 million women in the US and is commonly associated with infertility and pelvic pain. One of the major hallmarks of uterine diseases is disruption of steroid hormone control of uterine cell proliferation and differentiation. Using high density DNA microarray analysis, we have identified Mig-6 in the uterus as a target of SRC-1 and PR. Mig-6 regulates mouse fertility and the ability of P4 to attenuate E2 signaling using total and conditional ablation of Mig-6. The expression of Mig-6 in both level and cell specificity is dependent upon the menstrual cycle in the human endometrium. The expression of Mig- 6 is decreased in human endometriosis and endometrial cancer patients. The overall hypothesis of this proposal is that Mig-6 mediates the ability of P4 to inhibit endometrial cell proliferation caused by E2. The goal of this proposal will be to investigate the role of Mig-6 in the regulation of uterine endometrial function. Specific Aim 1 will investigate the role of Mig-6 in fertility and uterine physiology by the determination of the cell type specific expression and endocrine regulation of Mig-6 in the murine uterus and the characterization of the phenotype of mice with conditional ablation of Mig-6 in the reproductive tract. Specific Aim 2 will investigate the role of Mig-6 in the steroid regulation of uterine cell proliferation and gene expression. Specific Aim 3 will investigate the endometrial compartment in which Mig-6 regulates endometrial steroid responsiveness by using the tissue recombination technique. The understanding of the role of Mig-6 in steroid hormone regulation, early pregnancy, proliferation, and apoptosis of the uterus will provide a strategy to develop diagnostic and therapeutic tools for infertility, endometriosis, and endometrial cancer. PUBLIC HEALTH RELEVANCE: The expression of Mig-6 is decreased in human endometriosis and endometrial cancer patients. The goal of this proposal will be to investigate the role of Mig-6 in the regulation of steroid hormones in uterine endometrium function. The understanding of the role of Mig-6 in steroid hormone regulation, early pregnancy, proliferation, and apoptosis of the uterus will provide a strategy to develop diagnostic and therapeutic tools for infertility, endometriosis, and endometrial cancer.