The Genomic Function of Estrogen Receptor Beta in Endometriosis

雌激素受体β在子宫内膜异位症中的基因组功能

• 批准号: 10321675
• 负责人: Sang Jun Han
• 金额: $ 37.75万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-06 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321675
• 关键词: Affect; Apoptosis; Cell Death Signaling Process; Cells; Complex; Conceptions; Data; Deposition; Disease; EGF gene; Endometrial; Endometrium; Endothelial Cells; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Etiology; Gene Expression; Genes; Genomics; Growth; Growth Factor Gene; Human; Hypoxia Inducible Factor; Immunologic Surveillance; Infertility; Inflammasome; Inflammatory; Interferon-alpha; Knowledge; Lesion; Mediating; Mesenchymal; Molecular; NFAT5 protein; Names; Nuclear; Pathogenesis; Pathology; Pelvic Pain; Personal Satisfaction; Play; Productivity; Proteins; Receptor Signaling; Research Project Grants; Retrograde Menstruation; Role; S-Phase Fraction; Signal Transduction; Site; System; Tissues; Woman; angiogenesis; base; clinically significant; connective tissue growth factor; druggable target; endometriosis; gene network; genetic signature; hypoxia inducible factor 1; molecular targeted therapies; mouse model; new therapeutic target; novel; overexpression; prevent; reproductive; response; side effect; transcriptome

As endometriosis is an estrogen-dependent inflammatory disease, estrogen/estrogen receptor (ER) signaling has an essential role in the pathogenesis of endometriosis. We revealed that cytoplasmic ERβ interacts with the apoptosis machinery and inflammasome complex in endometriotic tissues to prevent apoptosis and stimulate cell proliferation activity, respectively. However, the function of nuclear ERβ in the pathogenesis of endometriosis has not yet been elucidated. To fill this gap in the scientific knowledge, we have determined the endometriotic tissue-specific ERβ-regulated transcriptome and ERβ-cistrome by using a novel endometrium-specific ERβ overexpression mouse model. Our new omics data provided three unique aspects of nuclear ERβ function that drive endometriosis progression. 1) The increases in anti-apoptosis signaling in the endometrium is one of the critical drivers that promote the progression of endometriosis. Our omics data revealed that the ERβ/Nuclear Factor of Activated T-cell 5 (NFAT5) complex directly downregulates the expression of N-Myc and STAT Interactor (NMI), which stimulates interferon (IFN)α-induced cell death signaling. In Aim 1, we will investigate the role of NMI in IFNα-induced cell death signaling in the normal endometrium and then identify whether the ERβ/NFAT5 complex downregulates the expression of NMI in endometriotic lesions to enhance endometriosis. Since epidermal growth factor receptor (EGFR) signaling is elevated in endometriotic tissue and involved in anti- apoptosis, we will also investigate the role of EGFR in the ERβ/NFAT5-mediated suppression of NMI expression in endometriotic tissues. 2) The epithelial-mesenchymal transition (EMT) is a critical step for endometriosis. Our omics data showed that the ERβ/Early Growth Response Protein 1 (EGR1) axis directly increased the expression of Fibrillin1 (FBN1), which is an activator of EMT, in ectopic lesions. In Aim 2, we will define the role of FBN1 in endometriosis-associated EMT in ectopic lesions and then determine whether the ERβ/EGR1 axis upregulates FBN1 gene expression in ectopic lesions to stimulate EMT in ectopic lesions. Since EGFR signaling also plays an essential role in EMT, the role of EGFR in ERβ/EGR1 axis-mediated EMT will be investigated. 3) To establish endometriosis, angiogenesis is activated in ectopic lesions. However, the molecular mechanism of estrogen- induced angiogenesis in ectopic lesions has not been elucidated. Our data revealed that ERβ elevated the expression of connective tissue growth factor (CTGF), which is the activator of hypoxia inducible factor 1a (HIF1A)-mediated angiogenesis, in ectopic lesions. In Aim 3, we will define the role of CTGF in endometriosis- associated angiogenesis and then determine whether the ERβ/HIF1A axis upregulates CTGF gene expression in ectopic lesions to stimulate angiogenesis. Since EGFR signaling also plays an essential role in angiogenesis, the role of EGFR in ERβ/HIF1A axis-mediated angiogenesis will be investigated. Collectively, these three ERβ gene networks will conceptionally advance our understanding of the molecular etiology of endometriosis and should provide new molecular therapeutic targets for alternative endometriosis therapies.

由于子宫内膜异位症是一种雌激素依赖性炎症性疾病，雌激素/雌激素受体 (ER) 信号传导 在子宫内膜异位症的发病机制中具有重要作用。我们发现细胞质 ERβ 与 子宫内膜异位组织中的细胞凋亡机制和炎性体复合物可防止细胞凋亡并刺激 分别是细胞增殖活性。然而，核ERβ在子宫内膜异位症发病机制中的作用 尚未阐明。为了填补这一科学知识的空白，我们确定了子宫内膜异位症 使用新型子宫内膜特异性 ERβ 构建组织特异性 ERβ 调节转录组和 ERβ-cistrome 过表达小鼠模型。我们的新组学数据提供了核 ERβ 功能的三个独特方面： 推动子宫内膜异位症进展。 1) 子宫内膜抗凋亡信号的增加是其中之一 促进子宫内膜异位症进展的关键驱动因素。我们的组学数据显示 ERβ/Nuclear 活化 T 细胞因子 5 (NFAT5) 复合物直接下调 N-Myc 和 STAT 的表达 Interactor (NMI)，可刺激干扰素 (IFN)α 诱导的细胞死亡信号传导。在目标 1 中，我们将调查 NMI 在正常子宫内膜中 IFNα 诱导的细胞死亡信号传导中的作用，然后确定是否 ERβ/NFAT5复合物下调子宫内膜异位病灶中NMI的表达，从而增强子宫内膜异位症。 由于表皮生长因子受体 (EGFR) 信号在子宫内膜异位组织中升高并参与抗- 细胞凋亡，我们还将研究 EGFR 在 ERβ/NFAT5 介导的 NMI 表达抑制中的作用 在子宫内膜异位组织中。 2）上皮间质转化（EMT）是子宫内膜异位症的关键步骤。我们的 组学数据显示 ERβ/早期生长反应蛋白 1 (EGR1) 轴直接增加表达 Fibrillin1 (FBN1) 是异位病变中 EMT 的激活剂。在目标 2 中，我们将定义 FBN1 在以下方面的作用： 异位病变中与子宫内膜异位症相关的 EMT，然后确定 ERβ/EGR1 轴是否上调 FBN1基因在异位病灶中表达，刺激异位病灶中的EMT。由于 EGFR 信号传导也发挥着 由于 EGFR 在 EMT 中发挥重要作用，因此将研究 EGFR 在 ERβ/EGR1 轴介导的 EMT 中的作用。 3）建立 子宫内膜异位症中，异位病变中的血管生成被激活。然而，雌激素的分子机制 异位病变中诱导的血管生成尚未阐明。我们的数据显示 ERβ 提高了 结缔组织生长因子 (CTGF) 的表达，CTGF 是缺氧诱导因子 1a 的激活剂 (HIF1A) 介导的异位病变中的血管生成。在目标 3 中，我们将定义 CTGF 在子宫内膜异位症中的作用 - 相关的血管生成，然后确定 ERβ/HIF1A 轴是否上调 CTGF 基因表达 在异位病变中刺激血管生成。由于 EGFR 信号传导在血管生成中也发挥着重要作用， 将研究 EGFR 在 ERβ/HIF1A 轴介导的血管生成中的作用。总的来说，这三个 ERβ 基因网络将在概念上促进我们对子宫内膜异位症分子病因学的理解 应该为子宫内膜异位症的替代疗法提供新的分子治疗靶点。