WNT signaling and stem cell activity in the myometrium

描述(由申请人提供)：子宫肌瘤(也称为子宫肌瘤)是子宫肌层的良性平滑肌肿瘤，被认为存在于高达70%的女性中。与临床显著的子宫肌瘤相关的症状包括盆腔疼痛、月经过多和/或痛经、贫血、反复妊娠丢失和不孕。子宫肌瘤是子宫切除术的主要原因，每年超过20万例。尽管子宫肌瘤的流行和子宫对女性生殖能力的重要性，人们对这种疾病的病因和发病机制知之甚少。此外，由于对肌瘤发生和发展的知识差距，阻碍了预防或治疗这种疾病的治疗方法的进步。子宫肌层被认为含有成体干细胞，在月经/发情周期、妊娠和产后子宫复旧期间，这些干细胞参与组织的生长/扩张和损伤修复。同样，肌瘤被认为是由单个突变的子宫肌层干细胞/祖细胞产生的；然而，导致这种变化的因素和机制尚不清楚。Wnt/�-catenin信号通路在干细胞功能调节和肿瘤发生中的作用广为人知。最近的研究表明，WnT/�-连环蛋白信号转导通路的不正确可能参与了肌瘤的形成和生长。本研究的目的是确定�-连接素活性异常的子宫肌干/祖细胞在子宫肌瘤发生发展中的作用。在这项建议中，重点放在研究肌瘤肿瘤的形成，而不是已建立的肿瘤的进展或维持。第一个特定的目的是通过使用表面标志物的富集法分离子宫肌干/祖细胞，并在体内外验证它们的干细胞活性。在第二个特定目标中，一种结构性活性(CA)形式的�-连环蛋白将在子宫肌干/祖细胞中表达，以研究其对肌瘤发展的影响。这些细胞将用于异种移植实验，以研究早期子宫肌瘤的形成，也将用于确定受CA�-连环蛋白影响的基因和信号通路。CA连环蛋白是一种转录共激活因子。本研究旨在研究子宫肌层干/祖细胞和失调的�-连环蛋白信号在子宫肌瘤发生发展中的作用，将为子宫肌瘤的病因和发病机制提供重要的认识，并可能为更好地治疗子宫肌瘤提供新的治疗手段。

DESCRIPTION (provided by applicant): Uterine leiomyomas (also known as uterine fibroids) are benign smooth muscle tumors of the myometrium that are thought to be present in up to 70% of women. Symptoms associated with clinically significant fibroids include, pelvic pain, excessive and/or painful menstruation, anemia, recurrent pregnancy loss and infertility. Uterine fibroids are the leading cause of hysterectomies, over 200,000 annually. Despite the prevalence of uterine leiomyomas and the importance of the uterus for a woman's reproductive capacity, little is known about the etiology and pathogenesis of the disease. Furthermore, because of the gap in knowledge surrounding leiomyoma development and progression, advancement in therapeutics to prevent or treat the disease is hindered. The myometrium is proposed to contain adult stem cells that participate in growth/expansion and damage repair of the tissue during the menstrual/estrous cycle, pregnancy and post-partum uterine involution. Likewise, leiomyomas are thought to arise from a single mutated myometrial stem/progenitor cell; however the factors and mechanisms that cause this change are unknown. WNT/�-Catenin signaling is well known for its role in regulating stem cell function and in carcinogenesis. Recent reports suggest that improper WNT/�- Catenin signaling might contribute to leiomyoma formation and growth. The goal of this proposal is to determine the contribution of myometrial stem/progenitor cells with dysregulated �-Catenin activity to leiomyoma development. In this proposal an emphasis is placed on studying leiomyoma tumor formation rather than progression or maintenance of established tumors. The first specific aim is to isolate myometrial stem/progenitor cells by enriching using surface markers and verify their stem cell activity in vitro and in vivo. In the second specific aim, a constitutively active (CA) form of �-Catenin will be expressed in myometrial stem/progenitor cells to study the impact on leiomyoma development. These cells will be used in xenotranplantation experiments to study early leiomyoma tumor formation and will also be used to determine genes and signaling pathways affected by CA �-Catenin, which is a transcriptional coactivator. The work proposed here, to study the role of myometrial stem/progenitor cells and dysregulated �-Catenin signaling in leiomyoma development, will provide important insight into the etiology and pathogenesis of the disease and may lead to new therapeutic tools to better manage uterine leiomyomas.