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重要的妇女健康问题。子宫内膜癌是最常见的妇科恶性肿瘤，也是女性第四常见的癌症。此外，子宫内膜异位症影响了美国约500万女性，通常与不孕症和盆腔疼痛有关。子宫疾病的主要标志之一是子宫细胞增殖和分化的类固醇激素控制的破坏。使用高密度DNA微阵列分析，我们已经将子宫中的Mig-6鉴定为SRC-1和PR的靶点。Mig-6调节小鼠生育力和P4使用Mig-6的完全和条件性消融减弱E2信号传导的能力。Mig-6在人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。该建议的总体假设是Mig-6介导P4抑制E2引起的子宫内膜细胞增殖的能力。本研究的目的是探讨Mig-6在调节子宫内膜功能中的作用。具体目标1将通过测定小鼠子宫中Mig-6的细胞类型特异性表达和内分泌调节以及生殖道中Mig-6条件性消融小鼠的表型表征来研究Mig-6在生育力和子宫生理学中的作用。具体目标2将研究Mig-6在子宫细胞增殖和基因表达的类固醇调节中的作用。具体目标3将调查子宫内膜隔室，其中米格-6调节子宫内膜类固醇反应性通过使用组织重组技术。了解Mig-6在类固醇激素调节、早期妊娠、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：在人类子宫内膜异位症和子宫内膜癌患者中，Mig-6的表达降低。本研究的目的是探讨Mig-6在类固醇激素调节子宫内膜功能中的作用。了解Mig-6在类固醇激素调节、早期妊娠、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.