Steroid Receptor Crosstalk and Pathogenesis of Uterine Fibroids

项目摘要 子宫肌瘤是育龄妇女最常见的妇科肿瘤。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。这个 调控子宫肌瘤发育和生长的分子机制尚不清楚， 这导致了有限的、非侵入性的治疗选择。因此，子宫肌瘤是主要的适应症。 在美国接受子宫切除术。迫切需要新的治疗干预措施，包括 选择性地瞄准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。 对乳腺和子宫内膜肿瘤的研究表明，类固醇激素的串扰可以- 支持肿瘤生长的特定信号与预后不良有关。我们的初步数据在 子宫表明GR与性激素受体、雌激素(ER)和 孕酮(PR)受体，已知的诱导子宫肌瘤生长的因素。对…的机械理解 糖皮质激素在子宫中的作用是有限的，因此，糖皮质激素信号转导代表着先前的 子宫肌瘤的发病机制尚不清楚。我们假设GR作为一种 子宫肌瘤发病机制中的关键转录调控因子。我们打算测试一下 我们的假设有三个具体目标。在具体目标1中，我们将定义负责 子宫肌瘤与正常子宫肌层细胞对糖皮质激素的不同反应。以特定的目标 2、明确GR调控子宫肌瘤细胞增殖的分子机制。最后， 目标3的目标将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。 这项拟议的工作具有创新性，因为我们的研究代表了对GR和GR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。通过定义流程， 糖皮质激素信号促进纤维瘤细胞增殖，这些研究将产生新的数据来促进我们的 了解这种高度流行的妇科疾病。成功完成这些研究可能会开启 开发有选择地针对GR调节因子或下游的干预措施的大门 GR信号分子在子宫肌瘤非侵入性治疗中的作用

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.