Uterine Leiomyoma Development in Mouse Models

描述(申请人提供)：子宫肌瘤(子宫肌瘤)是女性生殖道最常见的肿瘤。一些估计表明，超过50%的美国女性患有子宫肌瘤。此外，由于非裔美国女性患肌瘤的可能性是女性的2-3倍，因此在肌瘤的发病率方面存在着显著的差异。这些肿瘤可能非常痛苦，是女性不孕不育的主要原因。此外，由于这些肿瘤可以变得非常大，尽管子宫对于哺乳动物的繁殖是不可或缺的，但它们仍然是美国切除子宫的主要原因。尽管子宫肌瘤造成了医疗负担，但其病因和病理生理尚不清楚。我们已经培育出了突变小鼠，在其中，在生殖道组织中特异性地诱导了核连环蛋白信号。正常情况下，小鼠不会发生肌瘤；然而，这些突变的小鼠在8周大时会出现100%外显性的子宫平滑肌肿瘤。根据组织学和免疫组织化学标准，这些肿瘤表现出人类肌瘤的特征。β-catenin是Wnt信号的下游效应因子，在其活性失调后可导致器官和组织畸形及肿瘤的发生。在TSC2突变的Eker大鼠子宫肌瘤模型和大约50%的人子宫肌瘤中，小鼠也表达更高水平的mTOR，这表明mTOR激活可能是肌瘤发生发展的常见途径。我们将进一步研究这个小鼠模型，特别强调mTOR基因的表达和活性的调节，以便与其他缺乏肌层Lkb1的突变小鼠模型进行比较，Lkb1是Peutz-Jeghers综合征患者中突变的基因，TSC1也可以诱导mTOR活性和诱发子宫肌瘤，正如我们的初步结果所示。为了与Lkb1和TSC2缺失的子宫进行比较，我们建议在我们独特的小鼠模型中研究Wnt/？catenin调控失调对mTOR活性的细胞内机制和途径的影响。为了更好地了解子宫肌瘤的病因和发病机制，我们将研究突变的子宫肌层细胞中控制纤维化的分子机制，如细胞极性、细胞外 基质沉积和子宫肌层分化。我们将确定小鼠模型的哪些特征与人类肌瘤最相似，最适合进行临床前研究。最后，我们将确定Wnt/B-catenin信号的中断是否与人类子宫肌瘤的发生有关。这项研究的结果将为这些肿瘤的病因和进展提供新的见解，并为研究针对肌瘤发生和发展机制的治疗提供理论基础。

DESCRIPTION (provided by applicant): Uterine fibroids (leiomyomata uteri) are the most common tumors in the female reproductive tract. Some estimates indicate that more than 50% of American women have uterine fibroids. Additionally, there is a significant disparity in the incidence of fibroids since African-American women are 2-3 times more likely to develop fibroids. These tumors can be very painful and are a leading cause of infertility in women. Also, because these tumors can become very large, and although the uterus is indispensable for mammalian reproduction, they remain the main reason for hysterectomies in the US. Despite the healthcare burden caused by uterine fibroids, their etiology and pathophysiology are unknown. We have developed mutant mice in which nuclear ß-catenin signaling has been specifically induced in reproductive tract tissues. Normally, mice do not develop fibroids; however, these mutant mice develop smooth muscle tumors in their uteri with 100% penetrance by 8 weeks of age. These tumors exhibit characteristics of human fibroids by histological and immunohistochemical criteria. ß-Catenin, a well-known downstream effector of Wnt signaling, induces organ and tissue malformations and tumor development following dysregulation of its activity. The mice also express higher levels of mTor, as observed in the Tsc2-mutant Eker rat fibroid model and in approximately 50% of human fibroids, suggesting that mTor activation may be a common pathway in leiomyoma development. We will investigate this mouse model further, placing particular emphasis on the regulation of mTor gene expression and activity for comparison with other mutant mouse models lacking myometrial Lkb1, the gene mutated in patients with Peutz-Jeghers Syndrome, and Tsc1, both of which also induce mTor activity and induce uterine fibroids as shown in our preliminary results. We propose to investigate the intracellular mechanisms and pathways affected by dysregulated Wnt/ß-catenin in our unique mouse model that induce mTor activity for comparison with Lkb1- and Tsc2-deleted uteri. To better understand the etiology and pathogenesis of fibroids, we will study the molecular mechanisms controlling fibrosis in the mutant myometrial cells such as cell polarity, extracellular matrix deposition, and myometrial differentiation. We will determine which characteristics of the mouse models most closely resemble human leiomyomas and are best suited for preclinical studies. Lastly, we will determine whether disrupted Wnt/ß-catenin signaling contributes to human leiomyoma development. The results from the studies in this proposal will provide new insights into the etiology and progression of these tumors, as well as provide the rationale for investigating therapies targeting the mechanisms involved in leiomyoma development and progression.