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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：
10264278
负责人：
Shannon D Whirledge
金额：
$ 3.08万
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/10264278
关键词：
Age Benign Cell Proliferation Cells Data Endometrial Neoplasms Estrogen Receptors Female Genital Diseases Female Genital Neoplasms Fibroid Tumor Functional disorder Gene Expression Genetic Transcription Glucocorticoid Receptor Glucocorticoids Goals Gonadal Steroid Hormones Growth Growth and Development function Gynecologic Hormone Receptor Hysterectomy Investigation Leiomyoma Mammary Neoplasms Molecular Myometrial Ovarian hormone Pathogenesis Pathway interactions Process Progesterone Receptors Prognosis Signal Transduction Signaling Molecule Steroid Receptors Testing Therapeutic United States Uterine Fibroids Uterine Neoplasms Uterus Woman Women&apos s Health Work innovation myometrium novel therapeutic intervention receptor function reproductive response steroid hormone steroid hormone receptor therapy development 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.

项目总结