Endometriosis and Retinoids

子宫内膜异位症和类维生素A

• 批准号: 9376221
• 负责人: Serdar E. Bulun
• 金额: $ 6.83万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9376221
• 关键词: Affect; Agonist; Animals; Apoptosis; Binding Sites; Biological; Biological Models; Biological Process; Cell Cycle; Cell Differentiation process; Cell Line; Cell Proliferation; Cell Survival; Cells; Cessation of life; ChIP-seq; DNA; DNA Methylation; DNA Modification Methylases; Data; Decidual Cell Reactions; Defect; Development; Disease; Disease Progression; Endometrial; Endometrium; Enzymes; Epigenetic Process; Epithelial Cells; Estradiol; Estrogen Receptor beta; Estrogens; Etiology; Eye; Faculty; Functional disorder; Funding; Future Generations; Gene Expression; Gene Targeting; Genes; Goals; Grant; Hormones; In Vitro; Incidence; Individual; Indwelling Catheter; Infertility; Inflammatory; Instruction; Lead; Ligands; Mediating; Messenger RNA; Metabolism; Methylation; Michigan; Molecular; Nature; Nuclear Receptors; Operative Surgical Procedures; Organ; Ovarian; Papio; Pathogenesis; Pathologic; Pathology; Pathway interactions; Pelvic Pain; Pelvis; Peroxisome Proliferator-Activated Receptors; Phase; Physiological; Physiology; Prevention strategy; Production; Progesterone; Proteins; Proto-Oncogene Proteins c-akt; Regimen; Regulation; Replacement Therapy; Research; Resistance; Retinoids; Role; Signal Transduction; Stem cells; Steroids; Symptoms; Tetanus Helper Peptide; Therapeutic; Tissues; Tretinoin; Universities; Woman; alternative treatment; beta catenin; bone; design; endometriosis; experimental study; gene function; gene product; genome-wide; genome-wide analysis; in vivo; member; molecular marker; novel; novel therapeutics; promoter; response; retinoic acid receptor alpha; standard care; steroid hormone; targeted treatment; tissue culture; treatment strategy; uptake

Endometriosis, the pathologic endometrium-IIke tissue on pelvic organs, develops and persists in part due to defective apoptosis and is associated with pelvic pain and infertility. Our overall hypothesis is that defective steroid hormone and RA signaling is responsible for the abnormal reprogramming of endomethotic cells. We propose 3 aims. 1) To determine whether RORB deficiency, a consequence of progesterone resistance, is responsible for altered cell survival and differentiation in endometriosis. We uncovered a novel nuclear receptor (RORB), highly upregulated in response to progesterone in healthy cells, but absent in endometriotic cells. RORB regulates the differentiation of progenitor cells in the eye and in the bone in response to RA gradients, but has gone unnoticed in the endometrium. Our preliminary data suggest this progesterone-sensitive gene elicits the differentiation of endometrial stem cells in response to both progesterone and RA. We predict the loss of RORB in endometrial stem cells gives rise to diseased cells with altered differentiation and survival. We will determine the binding sites of RORB using CHIP-seq, and evaluate the in vivo and in vitro roles of RORB in healthy and diseased tissues to ascertain how progesterone and RA signaling coordinate biological changes in endometriosis. 2) To define the biological roles of key ERß target genes in endometriosis. ERß is one of the most significant targets affected by DNA methylation, and the loss of methylation across its promoter results in pathologic expression of ERß and altered response to estrogen. Preliminary ChlP-seq and microarray studies identified the enzymes RERG and SGK1 as unique targets of ERß, and suggested these genes mediate pro- inflammatory and pro-survival signaling in response to estrogen. We hypothesize the abnormal expression of these genes alters estrogen- and cell cycle-dependent gene expression and function. We will determine the molecular mechanism by which RERG and SGK1 contribute to the pathogenesis of endometriosis, as emerging therapies targeting these two enzymes would provide alternative treatment strategies for the disease. 3) To determine the mechanisms underlying steroid hormone and RA-dependent DNA methylation that are fundamental to endometriosis etiology. Our preliminary data identified large-scale differences in DNA methylation after the establishment of the disease. We hypothesize that key defects in methylation are already established or triggered in the eutopic endometrium of women destined to develop endometriosis. Using high throughput strategies to examine individual cells, this aim will examine the methylation status of key genes, and the body of enzymes that directly manipulate the methylation landscape in response to steroid hormones, RA and their nuclear receptors and focus on the DNMTs, which methylate DNA and the TETs, which demethylate DNA. The genome-wide effects of steroids and RA has not been well understood; however the unique epigenetic nature of endometriosis suggests that a genome-wide study of these enzymes will unveil the most critical targets that trigger the progression of the disease.

子宫内膜异位症是盆腔器官上类似子宫内膜的病理组织，其发生和持续存在的部分原因是 有缺陷的细胞凋亡并与盆腔疼痛和不孕有关。我们的总体假设是有缺陷的。 类固醇激素和 RA 信号传导导致子宫内膜细胞的异常重编程。 1) 确定 RORB 缺乏（黄体酮抵抗的结果）是否与 我们发现了一种新的核受体，与子宫内膜异位症中细胞存活和分化的改变有关。 (RORB)，在健康细胞中响应黄体酮而高度上调，但在子宫内膜异位细胞中不存在。 RORB 响应 RA 梯度调节眼睛和骨骼中祖细胞的分化， 但我们的初步数据表明这种孕激素敏感基因在子宫内膜中未被注意到。 引起子宫内膜干细胞对孕酮和 RA 的分化。我们预测。 子宫内膜干细胞中 RORB 的丧失会导致患病细胞的分化和存活。 将使用CHIP-seq确定RORB的结合位点，并评估RORB在体内和体外的作用 健康和患病组织以确定黄体酮和 RA 信号如何协调生物变化 2) 定义关键 ERß 靶基因在子宫内膜异位症中的生物学作用。 受 DNA 甲基化影响的最重要靶标，其启动子甲基化的丧失会导致 ERß 的病理表达和对雌激素反应的初步 ChlP-seq 和微阵列研究。 确定酶 RERG 和 SGK1 作为 ERß 的独特靶标，并建议这些基因介导亲 我们欺负了雌激素的异常表达。 这些基因改变雌激素和细胞周期依赖性基因的表达和功能。 RERG 和 SGK1 促进子宫内膜异位症发病机制的分子机制 针对这两种酶的疗法将为该疾病提供替代治疗策略。 确定类固醇激素和 RA 依赖性 DNA 甲基化的潜在机制 我们的初步数据确定了 DNA 的大规模差异。 疾病发生后的甲基化我们已经合作，甲基化的关键缺陷已经存在。 在注定会患子宫内膜异位症的妇女的在位子宫内膜中建立或触发。 检查单个细胞的通量策略，该目标将检查关键基因的甲基化状态，以及 直接操纵甲基化景观以响应类固醇激素 RA 的酶体 及其核受体，重点关注 DNMT（使 DNA 甲基化）和 TET（使 DNA 去甲基化） DNA。类固醇和 RA 对全基因组的影响尚未得到充分了解。 子宫内膜异位症的表观遗传性质表明，对这些酶进行全基因组研究将揭示最重要的 触发疾病进展的关键目标。