Steroid Receptor Crosstalk and Pathogenesis of Uterine Fibroids

类固醇受体串扰与子宫肌瘤的发病机制

基本信息

批准号：
10058465
负责人：
Shannon D Whirledge
金额：
$ 38.49万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-02 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10058465
关键词：
Age Benign Biological Availability Cell Proliferation Cells ChIP-seq Co-Immunoprecipitations Common Neoplasm Data Endometrial Neoplasms Estrogen Receptors Estrogens Female Genital Diseases Female Genital Neoplasms Fibroid Tumor Functional disorder Gene Expression Genes Genetic Transcription Genomic Segment Glucocorticoid Receptor Glucocorticoids Goals Gonadal Steroid Hormones Growth Growth and Development function Gynecologic Hormone Receptor Hydrocortisone Hysterectomy Investigation Leiomyoma Ligands Mammary Neoplasms Mass Spectrum Analysis Mediating Medical Molecular Mus Myometrial Ovarian hormone Parents Pathogenesis Pathologic Pathway interactions Phosphorylation Physiological Post-Translational Protein Processing Prevalence Process Progesterone Progesterone Receptors Protein Isoforms Receptor Activation Regulation Severities Signal Transduction Signaling Molecule Steroid Receptors Stream Symptoms Testing Therapeutic Tissues United States Uterine Fibroids Uterine Neoplasms Uterus Woman Women&apos s Health Work base cell type enzyme activity experimental study functional plasticity innovation knock-down myometrium novel novel therapeutic intervention outcome forecast receptor receptor binding receptor expression receptor function reproductive response steroid hormone steroid hormone receptor targeted treatment therapy development transcriptome sequencing transcriptomics tumor tumor growth

项目摘要

Project Summary Uterine fibroids (leiomyomoas) are the most common gynecologic tumor in women of reproductive age. Although these tumors are considered benign, they cause significant gynecologic and reproductive dysfunction. The molecular mechanisms that regulate the development and growth of uterine fibroids are not well-understood, which has resulted in limited, non-invasive therapeutic options. As such, uterine fibroids are the leading indication for hysterectomy in the United States. There is a critical need for new therapeutic interventions that involve selectively targeting the pathways that promote fibroid growth. We have recently discovered that activation of the glucocorticoid receptor (GR) promotes uterine fibroid cell proliferation. Moreover, we found that glucocorticoids induce a unique transcriptional response in uterine fibroid cells compared to normal myometrium. Studies in tumors of the breast and endometrium demonstrates that steroid hormone crosstalk allows context- specific signaling supporting tumor growth and is associated with a poor prognosis. Our preliminary data in the uterus indicates that GR demonstrates crosstalk with the sex hormone receptors, estrogen (ER) and progesterone (PR) receptor, known factors that induce uterine fibroid growth. A mechanistic understanding of glucocorticoid action in the uterus is limited, and thus, glucocorticoid signaling represents a previously unexplored pathway contributing to the pathogenesis of uterine fibroids. We hypothesize that GR functions as a critical transcriptional regulatory factor contributing to the pathogenesis of uterine fibroids. We propose to test our hypotheses in three specific aims. In Specific Aim 1, we will define the mechanisms responsible for the differential responses to glucocorticoids in uterine fibroids compared to normal myometrial cells. In Specific Aim 2, we will define the molecular mechanism by which GR regulates uterine fibroid cell proliferation. Finally, the goal of Aim 3 will be to discover how steroid hormone crosstalk regulates gene expression in uterine fibroid cells. The proposed work is innovative because our studies represent the first investigation into the actions of GR and the interplay of steroid hormone receptors in uterine fibroid cells. By defining the processes by which glucocorticoid signaling promotes fibroid cell proliferation, these studies will generate new data to advance our understanding of this highly prevalent gynecological disease. Successful completion of these studies may open the door to the development of interventions that selectively target GR regulatory factors or down-stream signaling molecules of GR for the non-invasive treatment of uterine fibroids.

项目概要子宫肌瘤（平滑肌瘤）是育龄妇女中最常见的妇科肿瘤。虽然这些肿瘤被认为是良性的，它们会导致严重的妇科和生殖功能障碍。这调节子宫肌瘤发育和生长的分子机制尚不清楚，这导致非侵入性治疗选择有限。因此，子宫肌瘤是主要适应症在美国进行子宫切除术。迫切需要新的治疗干预措施，其中包括选择性地针对促进肌瘤生长的途径。我们最近发现激活糖皮质激素受体（GR）促进子宫肌瘤细胞增殖。此外，我们发现与正常子宫肌层相比，糖皮质激素在子宫肌瘤细胞中诱导独特的转录反应。对乳腺癌和子宫内膜肿瘤的研究表明，类固醇激素的串扰可以使背景- 支持肿瘤生长的特定信号传导并与不良预后相关。我们的初步数据在子宫表明 GR 与性激素受体、雌激素 (ER) 和黄体酮（PR）受体，已知的诱导子宫肌瘤生长的因素。机械性的理解糖皮质激素在子宫中的作用是有限的，因此，糖皮质激素信号传导代表了以前的导致子宫肌瘤发病机制的未探索途径。我们假设 GR 的功能是有助于子宫肌瘤发病机制的关键转录调节因子。我们建议测试我们针对三个具体目标的假设。在具体目标 1 中，我们将定义负责的机制与正常子宫肌细胞相比，子宫肌瘤对糖皮质激素的反应不同。特定目标 2、我们将明确GR调节子宫肌瘤细胞增殖的分子机制。最后，目标 3 的目标是发现类固醇激素串扰如何调节子宫肌瘤细胞中的基因表达。拟议的工作具有创新性，因为我们的研究代表了对 GR 和子宫肌瘤细胞中类固醇激素受体的相互作用。通过定义流程糖皮质激素信号传导促进肌瘤细胞增殖，这些研究将产生新的数据来推进我们的研究了解这种高度流行的妇科疾病。成功完成这些研究可能会打开开发选择性针对遗传资源监管因素或下游干预措施的大门 GR 信号分子用于子宫肌瘤的非侵入性治疗。