Project 1: Steroid Hormone Action in Uterine Leiomyoma

子宫肌瘤在美国约77%的女性中发生，可导致严重的发病率和 不孕不育。到目前为止，除了子宫切除术外，还没有有效的治疗子宫肌瘤的方法。在此应用程序中，我们希望 在细胞和分子水平上更好地了解子宫肌瘤生长背后的生物学。具体来说， 有证据表明，黄体酮激素会导致肌瘤生长，一旦我们了解了黄体酮是如何， 通过其受体PR促进肌瘤生长，我们可以开始研究抑制这一过程的方法。我们有 黄体酮可以激活AKT途径的收集证据表明，AKT途径与细胞 扩散和生存。此外，我们还发现，通过PR，黄体酮可以减弱 转录因子FOXOI，它是AKT途径的成员，也是抑制细胞的分子 增殖并促进细胞死亡。有鉴于此，我们已经收集了初步证据来测试 化合物，一种AKT抑制剂，用于治疗动物模型的肌瘤。我们观察到AKT抑制剂 在免疫功能低下的小鼠中生长的肌瘤会导致显著的组织坏死。在这份提案中， 我们假设黄体酮既可以在非基因组水平(信号事件)起作用，也可以在基因组水平(基因)起作用。 以促进肌瘤的生长。它通过靶向AKT信号通路和下游效应器来实现这一点， 福克斯。因此，抑制这一途径应该提供一种抑制肌瘤生长和促进肌瘤生长的方法。 组织死亡。为了检验这一假设，我们提出了三个目标。特定目标1将调查澄清 FOXOI对BM基因作用的PR减弱机制 (细胞死亡)。特定目标2将探索孕酮如何激活AKT途径，以及下列哪些结果 抑制这一途径会影响细胞的增殖。特异靶3研究AKT抑制剂在 诱导子宫肌瘤细胞和免疫缺陷生长的人子宫肌瘤组织凋亡 老鼠。 相关性(请参阅说明)： 在美国，数以百万计的妇女受到症状性子宫肌瘤的影响，导致严重的发病率。 本项目的研究探索了一个重要的信号通路，即PI3K/AKT/F0X01，它是由 黄体酮与细胞的增殖和存活有关。这项研究将提供一个潜在的 PR促进子宫肌瘤生长的作用机制及其转化潜能 子宫肌瘤的治疗。； 项目/

Uterine leiomyomas occur in approximately 77% of all women in the United States and can cause severe morbidity and infertility. To date, there is no effective treatment for leiomyomas besides hysterectomies. In this application, we hope to better understand the biology behind uterine leiomyoma growth at the cellular and molecular level. Specifically, there is evidence that the hormone progesterone causes leiomyomas to grow and once we understand how progesterone, through its receptor, PR, promotes leiomyoma growth, we can begin to study ways to inhibit this process. We have gathered evidence that progesterone can activate the AKT pathway which is a pathway that is involved in cell proliferation and survival. In addition, we have found that progesterone, through PR, can attenuate the action of a transcription factor, FOXOI, which is a member ofthe AKT pathway as well as a molecule that inhibits cell proliferation and promotes cell death. In light of this, we have gathered preliminary evidence testing the efficacy of a chemical compound, an AKT inhibitor for treating leiomyomas in an animal model. We observe that the AKT inhibitor causes significant tissue necrosis in leiomyomas that have been grown in immunocompromised mice. In this proposal, we hypothesize that progesterone can act at both non-genomic (signaling events) as well as genomic (at the gene) levels to promote leiomyoma growth. It does this by targeting the AKT signaling pathway and the downstream effector, FOXOI. Thus, inhibition of this pathway should provide a means of inhibiting leiomyoma growth and promoting tissue death. To test this hypothesis, we propose three aims. Specific aim 1 will investigate the elucidating the mechanisms that are involved in PR attenuation of FOXOI action on a gene called BM, that is involved in apoptosis (cell death). Specific aim 2 will explore how progesterone activates the AKT pathway and what the consquence of inhibiting this pathway would be on cell proliferation. Specific aim 3 investigates the efficacy of the AKT inhibitor in inducing apoptosis in leiomyoma cells as well as human leiomyoma tissues that are growing in immunocompromised mice. RELEVANCE (See instructions): Millions of women in the US are affected by symptomatic uterine leiomyomata causing significant morbidity. The studies in this project explore an important signaling pathway, PI3K/AKT/F0X01, that is activated by progesterone and associated with cell proliferation and survival. This study will provide a potential mechanism of action of PR in promoting growth of leiomyomas and translate these data into a potential treatment nf leiomyomas. ; PROJEeT/