Endocrine disruption of myometrial stem cell activities

子宫肌干细胞活性的内分泌干扰

• 批准号: 8711586
• 负责人: JOSE M. TEIXEIRA
• 金额: $ 37.98万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711586
• 关键词: Adipocytes; Adipose tissue; Adult; Affect; African American; Alleles; American; Biology; Birth; Cell physiology; Cells; Complex; Conditioned Culture Media; Development; Diethylstilbestrol; Disease; Disease Progression; Duct (organ) structure; Dysmenorrhea; Endocrine Disruptors; Endocrine disruption; Endometrial; Endometrium; Environmental Estrogen; Environmental Exposure; Epigenetic Process; Estrous Cycle; Etiology; Exposure to; Fetus; Fibroid Tumor; Functional disorder; Gene Expression; Genes; Genistein; Healthcare; Homeostasis; Hormonal; Human; Hyperplasia; Hysterectomy; In Vitro; Infertility; Knowledge; Lead; Learning; Leiomyoma; Link; Longevity; Luciferases; Mammals; Menstrual cycle; Mesenchyme; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle satellite cell; Myometrial; Natural regeneration; Neonatal; Nuclear; Ovarian Steroid Hormone; Ovariectomy; Pathogenesis; Pathology; Pathway interactions; Pelvic Pain; Perinatal; Perinatal Exposure; Phenotype; Plastics; Play; Pregnancy; Primates; Principal Investigator; Process; Reporter; Reproduction; Role; Sexual Maturation; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Source; Stem cells; Stromal sarcoma; Structure of paramesonephric duct; Testing; Therapeutic Intervention; Time; Tissues; United States; Uterine Fibroids; Uterine hemorrhage; Uterus; Woman; base; bisphenol A; care burden; chronic pelvic pain; gain of function; in vivo; injury and repair; loss of function; mouse model; myometrium; pluripotency; promoter; regenerative; reproductive; reproductive function; research study; response; stem cell niche; stemness; treatment strategy; uterine smooth muscle cell

DESCRIPTION (provided by applicant): The adult uterus undergoes repeated cycles of "injury and repair" in response to hormonal signals during the estrous cycle in mice (or the menstrual cycle in primates) numerous times in a normal mammalian reproductive lifespan, as well as during pregnancy when it grows ten-fold to accommodate the fetus. Although this process of remodeling is essential for reproduction, the molecular mechanisms involved are largely unknown, particularly in primates where the top layer of the endometrium is shed and regenerated every month. The principal investigators have shown that conditional deletion of ¿-catenin in the Mullerian duct mesenchyme results in a progressive replacement of uterine smooth muscle cells in the myometrium with adipose tissue. They have also shown that the converse experiment with conditional expression of a gain-of-function allele of ¿-catenin results in myometrial smooth muscle hyperplasia and development of stromal sarcomas and leiomyoma's (uterine fibroids). Both phenotypes were observed only after mice entered sexual maturity, suggesting that the mechanisms disrupted in these mice are regulated by ovarian steroid hormones. The principal investigators hypothesize that disruption of the nuclear function of ¿-catenin, a key determinant of stemness in many stem cell microenvironments, in myometrial stem cells leads to these uterine pathologies. They have identified the regenerative myometrial smooth muscle stem cells in mice and in humans and propose to investigate whether endocrine disruptors (1) impact the differentiation and pluripotency of myometrial stem cells in vitro and in vivo during cycling, pregnancy, and leiomyoma development; (2) dysregulate the molecular mechanisms of Wnt/¿-catenin signaling in our gain-of-function and loss-of-function models; and (3) alter the differentiation and pluripotency of myometrial stem cells during the perinatal window of myometrial development. The results of these experiments will help determine whether endocrine disruptors have a significant impact on the differentiation and function of myometrial stem cells. Performing these experiments in unique mouse models of dysregulated Wnt/¿-catenin signaling will also help determine which of the molecular mechanisms used by ¿-catenin, during normal and conditionally disrupted differentiation and in the adult activities of the myometrial stem cells, are affected. The principal investigator predict that an environmentally relevant level of exposure to endocrine disruptors plays an important role in uterine biology, particularly at the myometrial stem cell level and its contribution to uteine fibroid etiology and pathophysiology.

描述（由申请人提供）：在正常的哺乳动物生殖周期中，成年子宫在小鼠的发情周期（或灵长类动物的月经周期）中多次响应激素信号，经历“损伤和修复”的重复周期，以及在怀孕期间，当它增长十倍以适应胎儿时。尽管这种重塑过程对生殖至关重要，但其分子机制在很大程度上是未知的，特别是在灵长类动物中，子宫内膜顶层每个月都会脱落和再生。主要研究人员已经证明，缪勒管间质中有条件地缺失¿-catenin会导致子宫肌层中的子宫平滑肌细胞逐渐被脂肪组织取代。他们还表明，有条件表达-catenin的功能获得等位基因的反向实验导致子宫内膜平滑肌增生和间质肉瘤和平滑肌瘤（子宫肌瘤）的发展。这两种表型都是在小鼠进入性成熟后才观察到的，这表明这些小鼠体内被破坏的机制是由卵巢类固醇激素调节的。主要研究人员假设，在子宫肌瘤干细胞中，在许多干细胞微环境中决定干细胞性的关键因素-catenin的细胞核功能的破坏导致了这些子宫病变。他们已经在小鼠和人类身上发现了再生的子宫肌瘤平滑肌干细胞，并提出研究内分泌干扰物是否会影响子宫肌瘤干细胞在体外和体内的分化和多能性，包括周期、妊娠和平滑肌瘤的发展；(2)在我们的功能获得和功能丧失模型中失调Wnt/¿-catenin信号的分子机制；(3)在围产期子宫肌发育窗口期改变子宫肌干细胞的分化和多能性。这些实验的结果将有助于确定内分泌干扰物是否对子宫肌瘤干细胞的分化和功能有显著影响。在Wnt/ -catenin信号失调的独特小鼠模型中进行这些实验也将有助于确定-catenin在正常和条件中断分化过程中使用的分子机制，以及在肌内膜干细胞的成体活动中受到影响。首席研究员预测，环境相关水平的内分泌干扰物暴露在子宫生物学中起着重要作用，特别是在子宫肌瘤干细胞水平及其对子宫肌瘤病因学和病理生理学的贡献。