Uterine Leiomyoma Development in Mouse Models

描述（由申请人提供）：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%的美国妇女患有子宫肌瘤。此外，肌瘤的发病率存在显着差异，因为非洲裔美国妇女患肌瘤的可能性高出2-3倍。这些肿瘤可能非常痛苦，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，尽管子宫是哺乳动物繁殖不可或缺的，但它们仍然是美国子宫切除术的主要原因。尽管子宫肌瘤造成医疗负担，但其病因和病理生理学尚不清楚。我们已经开发了突变小鼠，其中核连环蛋白信号传导在生殖道组织中被特异性诱导。正常情况下，小鼠不会发展成纤维瘤;然而，这些突变小鼠在8周龄时在其子宫中发展成平滑肌肿瘤，并具有100%的存活率。通过组织学和免疫组化标准，这些肿瘤表现出人类纤维瘤的特征。连环蛋白是一种众所周知的Wnt信号传导的下游效应物，在其活性失调后诱导器官和组织畸形以及肿瘤发展。小鼠还表达更高水平的mTor，如在Tsc 2突变Eker大鼠纤维瘤模型和约50%的人类纤维瘤中所观察到的，这表明mTor激活可能是平滑肌瘤发展中的常见途径。我们将进一步研究这种小鼠模型，特别强调mTor基因表达和活性的调节，以与缺乏子宫肌层Lkb 1的其他突变小鼠模型进行比较，该基因在Peutz-Jeghers综合征患者中突变，Tsc 1也诱导mTor活性并诱导子宫肌瘤，如我们的初步结果所示。我们建议在我们独特的小鼠模型中研究受失调的Wnt/<$-连环蛋白影响的细胞内机制和途径，该模型诱导mTor活性，以与Lkb 1和Tsc 2缺失的子宫进行比较。为了更好地了解子宫肌瘤的病因和发病机制，我们将研究控制突变子宫肌层细胞纤维化的分子机制，如细胞极性，细胞外基质， 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最接近人类平滑肌瘤，最适合临床前研究。最后，我们将确定是否破坏Wnt/β-catenin信号有助于人类平滑肌瘤的发展。本提案中的研究结果将为这些肿瘤的病因和进展提供新的见解，并为研究针对平滑肌瘤发展和进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 ¿-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.