Steroid Hormone Regulation of Uterine Function and Dysfunction

类固醇激素对子宫功能和功能障碍的调节

• 批准号: 7609077
• 负责人: Jae-Wook Jeong
• 金额: $ 26.1万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609077
• 关键词: Ablation; Adaptor Signaling Protein; Adenocarcinoma; Affect; Animals; Apoptosis; Attenuated; Biological Assay; Cancer Patient; Cell Proliferation; Cells; Communication; DNA Microarray Chip; Data; Development; Diagnostic; Disease; Endocrine; Endometrial; Endometrial Carcinoma; Endometrium; Epithelial; Epithelial Cells; Epithelium; Estrogens; Female; Fertility; Functional disorder; Gallbladder; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Goals; Growth Factor; Gynecologic; Human; Hyperplasia; Immunohistochemistry; Infertility; Kidney; Knock-out; Lung; Malignant Neoplasms; Mediating; Mediator of activation protein; Menstrual cycle; Microarray Analysis; Mitogens; Molecular; Mus; Organ; Ovarian; Pathology; Pelvic Pain; Phenotype; Physiology; Pregnancy; Progesterone; Progesterone Receptors; Recombinants; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Skin; Specificity; Steroids; Stimulus; Stomas; Stress; Techniques; Therapeutic; Time; Tissue Recombination; Tissues; United States; Uterine Diseases; Uterus; Western Blotting; Wild Type Mouse; Woman; Women' s Health; adenoma; angiogenesis; bile duct; capsule; cell type; cytokine; density; endometriosis; hormone regulation; implantation; mouse model; natural Blastocyst Implantation; nuclear receptor coactivator 1; public health relevance; reproductive; reproductive development; response; steroid hormone; therapy development; tool

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.

描述（由申请人提供）：女性生殖道疾病是女性健康的一个重大问题。子宫内膜癌是最常见的妇科恶性肿瘤，也是女性第四大常见癌症。此外，子宫内膜异位症影响着美国约500万女性，通常与不孕和盆腔疼痛有关。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被破坏。通过高密度DNA微阵列分析，我们发现子宫中的米格-6是SRC-1和PR的靶点。通过米格-6的全面和条件消融，米格-6调节小鼠的生育能力和P4减弱E2信号的能力。在人子宫内膜中，米格-6的表达水平和细胞特异性取决于月经周期。Mig- 6在人子宫内膜异位症和子宫内膜癌患者中表达降低。本提案的总体假设是，Mig-6介导P4抑制E2引起的子宫内膜细胞增殖的能力。本研究的目的是研究Mig-6在子宫内膜功能调节中的作用。特异性目的1将通过测定小鼠子宫中米格-6的细胞类型特异性表达和内分泌调节，以及在生殖道条件消融米格-6小鼠的表型特征，研究米格-6在生育和子宫生理中的作用。特异性目的2将探讨米格-6在类固醇调节子宫细胞增殖和基因表达中的作用。特异性目的3将通过组织重组技术研究Mig-6调节子宫内膜类固醇反应的子宫内膜腔室。了解米格-6在类固醇激素调节、早孕、子宫增殖和凋亡中的作用，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。本研究的目的是研究米格-6在类固醇激素对子宫内膜功能的调节中的作用。了解米格-6在类固醇激素调节、早孕、子宫增殖和凋亡中的作用，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。