Endocrine disruption of myometrial stem cell activities

子宫肌干细胞活性的内分泌干扰

基本信息

批准号：
8679137
负责人：
JOSE M. TEIXEIRA
金额：
$ 38.05万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8679137
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 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

项目摘要

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）：在正常哺乳动物的生殖寿命中，成年子宫在小鼠的发情周期（或灵长类动物的月经周期）期间，响应激素信号而经历多次“损伤和修复”的重复周期，以及在怀孕期间，它会生长十倍以适应胎儿，尽管这种重塑过程对于繁殖至关重要，但所涉及的分子机制在很大程度上尚不清楚，特别是在灵长类动物中。子宫内膜每个月都会脱落和再生，主要研究人员已经表明，有条件地删除 ¿苗勒氏管间充质中的β-连环蛋白导致子宫肌层中的子宫平滑肌细胞被脂肪组织组织逐渐取代。他们还表明，与功能获得等位基因的条件表达相反的实验。 β-连环蛋白导致子宫肌层平滑肌增生以及间质肉瘤和子宫肌瘤（子宫肌瘤）的发展，这两种表型仅在小鼠进入性成熟后才观察到，这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。 ¿ 核功能的破坏-连环蛋白是许多干细胞微环境中干性的关键决定因素，在子宫肌层干细胞中会导致这些子宫病变。他们在小鼠和人类中鉴定出了再生的子宫肌层平滑肌干细胞，并提议研究内分泌干扰物 (1) 是否会影响。子宫肌层干细胞在循环、妊娠和平滑肌瘤发育过程中的体外和体内分化和多能性；(2) 调节 Wnt/¿ -我们的功能获得和功能丧失模型中的连环蛋白信号传导；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存在。在独特的 Wnt/¿ 失调小鼠模型中进行这些实验对子宫肌层干细胞的分化和功能有重大影响。 -连环蛋白信号传导也将有助于确定 ¿ 使用的分子机制-连环蛋白在正常和条件性破坏的分化过程中以及在子宫肌层干细胞的成体活动中都会受到影响。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发挥着重要作用，特别是在子宫肌层干细胞中。细胞水平及其对子宫肌瘤病因学和病理生理学的贡献。