Endocrine disruption of myometrial stem cell activities

描述（由申请人提供）：在正常哺乳动物生殖寿命期间，成年子宫在小鼠的发情周期（或灵长类动物的月经周期）中多次经历对激素信号的“损伤和修复”的重复循环，以及在妊娠期间，当它增长10倍以容纳胎儿时。虽然这种重塑过程对生殖至关重要，但所涉及的分子机制在很大程度上是未知的，特别是在灵长类动物中，子宫内膜的顶层每个月都会脱落和再生。主要研究者已经表明，苗勒管间充质中的<$-连环蛋白的条件性缺失导致子宫肌层中的子宫平滑肌细胞被脂肪组织进行性替代。他们还表明，与条件性表达的功能获得性等位基因的<$-连环蛋白的匡威实验导致子宫肌层平滑肌增生和基质肉瘤和平滑肌瘤（子宫肌瘤）的发展。这两种表型仅在小鼠进入性成熟后观察到，表明这些小鼠中被破坏的机制受到卵巢类固醇激素的调节。主要研究人员假设，在子宫肌层干细胞中，连环蛋白（在许多干细胞微环境中是干细胞的关键决定因素）的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中鉴定了再生的子宫肌层平滑肌干细胞，并提出研究内分泌干扰物是否（1）在体外和体内循环、妊娠和平滑肌瘤发育期间影响子宫肌层干细胞的分化和多能性;（2）在我们的功能获得和功能丧失模型中失调Wnt/<$-连环蛋白信号传导的分子机制;以及（3）在子宫肌层发育的围产期窗口期间改变子宫肌层干细胞的分化和多能性。这些实验的结果将有助于确定内分泌干扰物是否对子宫肌层干细胞的分化和功能有显著影响。在Wnt/<$-连环蛋白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在正常和条件性破坏的分化期间以及在子宫肌层干细胞的成体活动中，<$-连环蛋白所使用的分子机制中的哪一种受到影响。主要研究者预测，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，特别是在子宫肌层干细胞水平及其对子宫肌瘤病因学和病理生理学的贡献。

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.