Uterine Leiomyoma Development in Mouse Models

描述（申请人提供）：子宫肌瘤（子宫平滑肌瘤）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非裔美国女性的2-3倍，因此在肌瘤发病率方面存在显著差异。这些肿瘤非常痛苦，是女性不孕的主要原因。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生殖是必不可少的，但它们仍然是美国子宫切除术的主要原因。尽管子宫肌瘤引起的医疗负担，其病因和病理生理尚不清楚。我们已经开发了突变小鼠，其中核¿-连环蛋白信号在生殖道组织中被特异性诱导。正常情况下，小鼠不会产生肌瘤；然而，这些突变小鼠在8周龄时子宫内出现平滑肌肿瘤，外显率为100%。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。-Catenin是一种众所周知的Wnt信号的下游效应物，在其活性失调后可诱导器官和组织畸形和肿瘤发展。正如在tsc2突变的Eker大鼠肌瘤模型和大约50%的人类肌瘤中观察到的那样，小鼠也表达更高水平的mTor，这表明mTor激活可能是平滑肌瘤发展的共同途径。我们将进一步研究该小鼠模型，特别强调mTor基因表达和活性的调控，并与其他缺乏myometrial Lkb1 （Peutz-Jeghers综合征患者中突变的基因）和Tsc1的突变小鼠模型进行比较，我们的初步结果表明，这两种突变小鼠模型也能诱导mTor活性并诱发子宫肌瘤。我们建议在我们独特的小鼠模型中研究受失调的Wnt/¿-catenin影响的细胞内机制和途径，以诱导mTor活性，并与Lkb1-和tsc2缺失的子宫进行比较。为了更好地了解肌瘤的病因和发病机制，我们将研究突变肌瘤细胞中控制纤维化的分子机制，如细胞极性、细胞外

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 ¿-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. ¿-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/¿-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/¿-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.