Estrogen Action in Normal and PCOS Endometrium

雌激素在正常和多囊卵巢综合征子宫内膜中的作用

• 批准号: 7315892
• 负责人: Bruce A Lessey
• 金额: $ 14.66万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7315892
• 关键词: Affect; Age; Androgen Receptor; Androgens; Binding; CD55 Antigens; Cell Line; Cells; Contraceptive Agents; Defect; Development; Down-Regulation; ERG gene; Endocrine System Diseases; Endometrial; Endometrial Hyperplasia; Endometrium; Enzymes; Epidermal Growth Factor; Epithelial; Epithelium; Equilibrium; Estrogen Receptors; Estrogens; Event; Exhibits; Failure; Family; Figs - dietary; Functional disorder; Funding; G-Protein-Coupled Receptors; Gene Targeting; Gonadal Steroid Hormones; Growth Factor; Growth Factor Receptors; Hand; Hormonal; Hormones; Human; Hyperinsulinism; Infertility; Insulin; Integrins; Ligands; MYBBP1A gene; Mammals; Mediating; Membrane; Menstrual cycle; Metabolism; Mitosis; Modeling; Molecular; Molecular Analysis; Nuclear; Nuclear Receptors; Ovarian; Pathway interactions; Performance; Phase; Plasma; Progesterone; Protein Family; Proteins; Receptor Up-Regulation; Risk; Role; Signal Pathway; Steroid Receptors; Stromal Cells; Syndrome; Testosterone; Thinking; Time; United States; Woman; Work; human tissue; implantation; improved; in vitro Model; in vivo; insight; natural Blastocyst Implantation; novel; paracrine; reproductive; research study; resistance mechanism; response; uterine receptivity

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-aged women. Women with PCOS exhibit poor reproductive performance and are at increased risk for endometrial hyperplasia. During the last funding periods, we described specific derangements in the endometrium of women with PCOS, including high levels of androgen receptors (AR), estrogen receptors (ER), and the pi6o coactivators. In this proposal, we are focused mainly on the role of estrogen and epidermal growth factor (EGF) in normal and PCOS endometrium. Estrogen has both positive and negative effects on implantation. Progesterone limits the action of estrogen through down-regulation of ER and up-regulation of enzymes that metabolize estrogen at the time of embryo attachment. Persistent estrogen actions inhibit expression of specific proteins thought to be essential for normal implantation. EGF family proteins, on the other hand, stimulate expression of implantation related proteins. We hypothesize that estrogen, acting through membrane associated pathways, stimulates the action of EGF family ligands. We will study for the first time a novel membrane-bound estrogen receptor, GPRso, in human endometrial epithelium and define the EGF-mediated signaling pathways elicited by estrogen binding to this G-protein coupled receptor. In Aim i. we will identify factors that influence the estrogen response during the menstrual cycle in normal and PCOS endometrium. In Aim 2. we will describe key effects of estrogen on normal and PCOS endometrium by determining the membrane and nuclear receptor mechanisms through which estrogen regulates the expression of estrogen response factors and other target genes. In Aim a. we will dissect the signaling pathways used by estrogen in regulating the early response gene, Cyr6i. Finally, in Aim 4. we will use in vivo and in vitro models to characterize the responsiveness to progesterone and estrogen and determine the functions of epithelial and stromal cells from normal and PCOS endometrium to identify paracrine factors that may underlie the regulatory dysfunction in PCOS. The experiments will utilize molecular analysis of a combination of human endometrial cell lines, primary cultures of human endometrial cells and human tissue explant models to achieve these aims. Understanding normal and abnormal mechanisms of sex steroid action in human endometrium will provide important insights toward the development, of improved infertility treatments and contraceptive approaches.

多囊卵巢综合症（PCOS）是育龄期最常见的内分泌疾病 女性。患有多囊卵巢综合症的女性生殖能力较差，患多囊卵巢综合症的风险增加 子宫内膜增生。在上一个资助期间，我们描述了具体的混乱情况 患有 PCOS 的女性的子宫内膜，包括高水平的雄激素受体 (AR)、雌激素受体 (ER) 和 pi6o 共激活剂。在本提案中，我们主要关注雌激素和 正常和 PCOS 子宫内膜中的表皮生长因子 (EGF)。雌激素既有积极作用，也有 对着床的负面影响。黄体酮通过下调雌激素的作用来限制雌激素的作用 ER 和胚胎附着时雌激素代谢酶的上调。执着的 雌激素的作用抑制了被认为对正常着床至关重要的特定蛋白质的表达。 另一方面，EGF 家族蛋白刺激植入相关蛋白的表达。我们 假设雌激素通过膜相关途径发挥作用，刺激 EGF 的作用 家族配体。我们将首次研究一种新型膜结合雌激素受体 GPRso 人类子宫内膜上皮并定义雌激素引发的 EGF 介导的信号通路 与该 G 蛋白偶联受体结合。在艾姆我。我们将确定影响雌激素的因素 正常和 PCOS 子宫内膜在月经周期期间的反应。在目标 2 中，我们将描述关键 通过测定膜和核来研究雌激素对正常和 PCOS 子宫内膜的影响 雌激素通过受体机制调节雌激素反应因子的表达 其他靶基因。在目标a.我们将剖析雌激素在调节 早期反应基因，Cyr6i。最后，在目标 4 中，我们将使用体内和体外模型来表征 对黄体酮和雌激素的反应并确定上皮细胞和基质细胞的功能 从正常子宫内膜和 PCOS 子宫内膜中鉴定可能构成调节的旁分泌因子 多囊卵巢综合症的功能障碍。该实验将利用人类组合的分子分析 子宫内膜细胞系、人类子宫内膜细胞的原代培养物和人类组织外植体模型 实现这些目标。了解人类性类固醇作用的正常和异常机制 子宫内膜将为改进不孕症治疗的发展提供重要见解 和避孕方法。