Project 1: Steroid Hormone Action in Uterine Leiomyoma

在美国，大约77%的妇女发生子宫平滑肌瘤，并可导致严重的发病率和 不孕迄今为止，除了子宫肌瘤切除术外，没有有效的治疗方法。在这个应用程序中，我们希望 以更好地了解子宫肌瘤生长背后的细胞和分子水平的生物学。具体地说， 有证据表明孕酮激素导致平滑肌瘤生长，一旦我们了解了孕酮， 通过其受体PR促进平滑肌瘤生长，我们可以开始研究抑制这一过程的方法。我们有 收集的证据表明，孕酮可以激活AKT途径，这是一种参与细胞凋亡的途径。 增殖和生存。此外，我们还发现，孕酮通过PR，可以减弱 转录因子FOXOI是AKT通路的成员，也是抑制细胞增殖的分子。 增殖并促进细胞死亡。有鉴于此，我们已经收集了初步证据， 化合物，AKT抑制剂，用于治疗动物模型中的平滑肌瘤。我们观察到AKT抑制剂 导致免疫功能低下小鼠体内生长的平滑肌瘤显著的组织坏死。在这一提议中， 我们假设孕酮可以在非基因组（信号事件）和基因组（基因）水平上起作用。 促进平滑肌瘤生长。它通过靶向AKT信号通路和下游效应子来实现这一点， 福克斯。因此，抑制该途径应该提供抑制平滑肌瘤生长和促进平滑肌瘤生长的手段。 组织死亡为了验证这一假设，我们提出了三个目标。具体目标1将研究阐明 参与PR减弱FOXOI作用于BM基因的机制，BM参与细胞凋亡 (cell死亡）。具体目标2将探讨孕激素如何激活AKT通路，以及 抑制这一途径将影响细胞增殖。具体目标3研究AKT抑制剂在以下中的功效： 诱导平滑肌瘤细胞以及在免疫缺陷中生长的人平滑肌瘤组织的凋亡， 小鼠 相关性（参见说明）： 在美国，数百万妇女受到有症状的子宫平滑肌瘤的影响，导致严重的发病率。 本项目中的研究探索了一个重要的信号通路，PI 3 K/AKT/F0 X 01，其被激活， 孕酮和与细胞增殖和存活相关。这项研究将提供一个潜在的 PR促进平滑肌瘤生长的作用机制，并将这些数据转化为潜在的 治疗子宫肌瘤。; 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/