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: 8059736
• 负责人: Jae-Wook Jeong
• 金额: $ 24.8万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 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/8059736
• 关键词: Ablation; Adaptor Signaling Protein; Adenocarcinoma; Affect; Animals; Apoptosis; Attenuated; Biological Assay; Cancer Patient; Cell Differentiation process; Cell Proliferation; Cells; Communication; DNA Microarray Chip; Data; Development; Diagnostic; Disease; Embryonic Development; 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; Health; 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; 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）：女性生殖道的疾病代表了重大的女性健康问题。子宫内膜癌是最常见的妇科恶性肿瘤，也是女性第四大癌症。此外，子宫内膜异位症影响了美国估计的500万妇女，通常与不育症和骨盆疼痛有关。子宫疾病的主要标志之一是破坏子宫细胞增殖和分化的类固醇激素控制。使用高密度DNA微阵列分析，我们已经将子宫中的MIG-6确定为SRC-1和PR的靶标。 MIG-6调节小鼠的生育能力以及P4使用MIG-6的总和烧蚀能够减轻E2信号的能力。 MIG-6在水平和细胞特异性上的表达取决于人子宫内膜中的月经周期。在人子宫内膜异位症和子宫内膜癌患者中，MIG-6的表达降低。该提议的总体假设是MIG-6介导P4抑制由E2引起的子宫内膜细胞增殖的能力。该提案的目的是研究MIG-6在子宫子宫内膜功能调节中的作用。具体目标1将通过确定MIG-6在鼠子宫中MIG-6的细胞类型表达和内分泌调节以及小鼠表型的表征，并通过在生殖道中有条件消融小鼠的表征来研究MIG-6在生育能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将研究子宫内膜室，其中MIG-6通过使用组织重组技术调节子宫内膜类固醇的反应性。对MIG-6在类固醇激素调节中的作用的理解将为子宫的早期妊娠，增殖和凋亡提供，以开发一种策略，以开发诊断性和治疗性工具，以进行不育，子宫内膜异位症和子宫内膜癌。公共卫生相关性：人子宫内膜异位症和子宫内膜癌患者的MIG-6的表达降低。该提案的目的是研究MIG-6在子宫内膜功能中的类固醇激素调节中的作用。对MIG-6在类固醇激素调节中的作用的理解将为子宫的早期妊娠，增殖和凋亡提供，以开发一种策略，以开发诊断性和治疗性工具，以进行不育，子宫内膜异位症和子宫内膜癌。