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：
10391705
负责人：
Shannon D Whirledge
金额：
$ 2.53万
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/10391705
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 Prognosis 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 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.

项目摘要子宫肌瘤（平滑肌瘤）是生殖年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，它们会引起明显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未得到很好的理解，这导致了有限的非侵入性治疗选择。因此，子宫肌瘤是领先的指示用于子宫切除术在美国。涉及新的治疗干预措施的急需有选择地靶向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）促进子宫肌瘤细胞的增殖。而且，我们发现与正常的子宫肌层相比，糖皮质激素诱导子宫肌瘤细胞的独特转录反应。对乳腺和子宫内膜肿瘤的研究表明，类固醇激素串扰允许背景 - 特定的信号支持肿瘤生长，并与预后不良有关。我们在子宫表明GR与性激素受体，雌激素（ER）和孕酮（PR）受体，诱导子宫肌瘤生长的已知因素。机械理解子宫中的糖皮质激素作用受到限制，因此，糖皮质激素信号传导代表先前未开发的途径，导致子宫肌瘤的发病机理。我们假设GR充当关键的转录调节因子有助于子宫肌瘤的发病机理。我们建议测试我们以三个特定目标的假设。在特定目标1中，我们将定义负责与正常的子宫肌层细胞相比，对子宫肌瘤中糖皮质激素的差异反应。在特定目标中 2，我们将定义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。拟议的工作是创新的，因为我们的研究代表了对GR和GR的行为的首次调查子宫肌瘤细胞中类固醇激素受体的相互作用。通过定义过程糖皮质激素信号传导促进肌瘤细胞的增殖，这些研究将产生新数据以促进我们的了解这种高度普遍的妇科疾病。这些研究的成功完成可能会开放开发干预措施的大门，这些干预措施有选择地针对GR调节因素或下游 GR的信号分子，用于对子宫肌瘤的非侵入性治疗。