WNT signaling and stem cell activity in the myometrium

子宫肌层中的 WNT 信号传导和干细胞活性

• 批准号: 8784659
• 负责人: Amanda Patterson
• 金额: $ 5.15万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8784659
• 关键词: Adult; Affect; Age; Anemia; Apoptosis; Benign; Birth; Cell physiology; Cells; Common Neoplasm; Development; Disease; Dysmenorrhea; Estrous Cycle; Etiology; Fetus; Fibroid Tumor; Frequencies; Gene Expression; Genes; Goals; Growth; Growth and Development function; Histologic; Human; Hyperplasia; Hypertrophy; Hysterectomy; In Vitro; Infertility; Knowledge; Label; Lead; Leiomyoma; MCAM gene; Maintenance; Menorrhagia; Menstruation; Mesenchyme; Methods; Mus; Muscle Cells; Mutate; Myometrial; Nuclear; Organ; Ovarian Steroid Hormone; Overweight; Pain; Pathogenesis; Pathway interactions; Pelvic Pain; Pelvis; Penetrance; Pericytes; Plastics; Pregnancy; Pregnancy loss; Prevalence; Process; Recurrence; Reporting; Research; Role; Signal Transduction; Signaling Pathway Gene; Smooth Muscle Tumor; Source; Stem cells; Surface; Symptoms; Techniques; Testing; Therapeutic; Tissues; Transcription Coactivator; Transgenic Mice; United States; Uterine Fibroids; Uterus; WNT Signaling Pathway; Woman; Work; adult stem cell; base; carcinogenesis; clinically significant; in vitro activity; in vivo; injury and repair; insight; myometrium; novel therapeutics; prevent; public health relevance; reproductive; research study; self-renewal; stem; therapeutic development; tissue repair; tool; tumor

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.

描述（由适用提供）：子宫平滑肌瘤（也称为子宫纤维）是肌层的良性平滑肌肿瘤，被认为在多达70％的女性中存在。与临床上显着的纤维相关的症状包括骨盆疼痛，过度和/或疼痛的月经，贫血，复发性妊娠丧失和不育。子宫纤维是子宫切除术的主要原因，尽管子宫平滑肌瘤患病率超过200,000，并且子宫对女性生殖能力的重要性，但对疾病的病因和发病机理知之甚少。此外，由于围绕平滑肌瘤发展和进展的知识存在差距，因此阻碍了预防或治疗疾病的理论发展。提议子宫肌层含有成年干细胞，这些干细胞参与月经/发情周期，妊娠和子宫后子宫疾病期间组织的生长/扩张和损害修复。同样，平滑肌瘤被认为是由单个突变的肌层茎/祖细胞引起的。但是，导致这种变化的因素和机制尚不清楚。 Wnt/�-蛋白蛋白信号传导以确定干细胞功能和癌变中的作用而闻名。最近的报道表明，Wnt/�-Catenin信号传导可能有助于平滑肌瘤的形成和生长。该提案的目的是确定肌层干/祖细胞对 - 帕宁肽活性对平滑肌瘤发育的贡献。在此提案中，重点是研究肿瘤形成平滑肌瘤，而不是对已建立肿瘤的进展或维持。第一个具体目的是通过使用表面标记富集并在体外和体内验证其干细胞活性来分离肌层干/祖细胞。在第二个特定目的中，在肌层干/祖细胞中将表达组成型活性（CA）形式 - 以研究对平滑肌瘤发育的影响。这些细胞将用于异种扁平化实验中，以研究早期的平滑肌瘤形成，还将用于确定受CA�-catenin影响的基因和信号通路，这是转录共激活剂。这里提出的工作，研究肌层干/祖细胞的作用以及失调的 - - 卡宁蛋白信号在平滑肌瘤发育中的作用，将为疾病的病因和发病机理提供重要的见解，并可能导致新的治疗工具以更好地管理子宫平滑肌瘤。