WNT signaling and stem cell activity in the myometrium

描述（由申请人提供）：子宫平滑肌瘤（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。与临床上显著的纤维瘤相关的症状包括骨盆疼痛、月经过多和/或疼痛、贫血、复发性流产和不孕症。子宫肌瘤是子宫切除术的主要原因，每年超过20万例。尽管子宫平滑肌瘤的患病率和子宫对女性生殖能力的重要性，但对该疾病的病因和发病机制知之甚少。此外，由于围绕平滑肌瘤发展和进展的知识的差距，阻碍了预防或治疗该疾病的治疗方法的进步。建议子宫肌层含有成体干细胞，其在月经/发情周期、妊娠和产后子宫复旧期间参与组织的生长/扩增和损伤修复。同样，平滑肌瘤被认为是由单一突变的子宫肌层干/祖细胞引起的;然而，引起这种变化的因素和机制尚不清楚。WNT/β-Catenin信号传导因其在调节干细胞功能和致癌中的作用而众所周知。最近的报道表明，不适当的WNT/β- Catenin信号可能有助于平滑肌瘤的形成和生长。本研究的目的是确定β-连环蛋白活性失调的子宫肌层干/祖细胞对平滑肌瘤发生的作用。在这个建议中，重点放在研究平滑肌瘤肿瘤的形成，而不是发展或维持已建立的肿瘤。第一个具体目标是通过使用表面标记物富集分离子宫肌层干/祖细胞，并在体外和体内验证其干细胞活性。在第二个具体目标中，组成型活性（CA）形式的β-连环蛋白将在子宫肌层干/祖细胞中表达，以研究对平滑肌瘤发育的影响。这些细胞将用于异种移植实验，以研究早期平滑肌瘤肿瘤的形成，也将用于确定受CA β-连环蛋白影响的基因和信号通路，CA β-连环蛋白是一种转录共激活因子。这里提出的工作，研究子宫肌层干/祖细胞和失调的β-连环蛋白信号在平滑肌瘤发展中的作用，将为疾病的病因和发病机制提供重要的见解，并可能导致新的治疗工具，以更好地管理子宫平滑肌瘤。

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.