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：
8390253
负责人：
JOSE M. TEIXEIRA
金额：
$ 43.68万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8390253
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. PUBLIC HEALTH RELEVANCE: Uterine fibroids afflict approximately 20% of American women during their reproductive years and are a significant source of pelvic pain, abnormal uterine bleeding, and infertility. Uterine fibroids are also the major reason for hysterectomies in the United States. Despite the major health care burden posed by uterine fibroids, very little is known about their cause or the best treatment strategies. The overall aims of the proposed studies are to understand the effects of environmental exposure to endocrine-disrupting compounds (EDCs) on the stem cells that are responsible for uterine fibroid development and determine whether therapeutic intervention at the stem cell level can lead to better management strategies for this disease.

描述（由适用提供）：成年子宫在小鼠（或在正常的哺乳动物生殖生命周期中）以及在怀孕期间多次在妊娠期间多次进行小鼠（或私有月经周期）的荷尔蒙信号的反复循环，以适应fetus。尽管这种重塑的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是未知的，尤其是在每月放出和再生子宫内膜顶层的主要中。首席研究人员表明，穆勒（Mullerian）管间充质中的有条件缺失 - 帕宁蛋白会导致用脂肪组织在子宫肌层中逐渐替代子宫平滑肌细胞。他们还表明，匡威实验的有条件表达的功能获得等位基因�-catenin导致肌层平滑肌增生以及基质肉瘤和平滑肌瘤（子宫纤维）的发展。仅在小鼠进入性成熟后才观察到两种表型，这表明这些小鼠中的机制受到了卵巢类固醇恐怖的调节。主要研究人员假设麦克调蛋白的核功能的破坏是许多干细胞微环境中干性干细胞中干性干细胞中干细胞中干细胞的核功能。他们已经确定了小鼠和人类中再生的肌层平滑肌干细胞，并提出了研究内分泌干扰物（1）是否会在循环，妊娠期间和体内产生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，Wnt/®信号传导的分子机制失调；（3）在肌层发育的围产期窗口中改变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肌层干细胞的分化和功能有重大影响。在正常和有条件地破坏的分化过程中以及在肌层干细胞的成年活性期间，在唯一的Wnt/catenin信号传导的独特小鼠模型中执行这些实验。主要研究者预测，与内分泌干扰物的环境相关水平在肾上腺生物学中起着重要作用，尤其是在肌层干细胞水平上及其对二元纤维化病因学和病理生理学的贡献。公共卫生相关性：子宫纤维在生殖年中大约20％的美国妇女苦苦挣扎，并且是骨盆疼痛，子宫出血异常和不孕症的重要来源。子宫纤维也是美国子宫切除术的主要原因。尽管伯恩（Burnen）由子宫纤维造成的主要医疗保健，但对其原因或最佳治疗策略知之甚少。拟议研究的总体目的是了解环境暴露于内分泌干扰物（EDC）对负责子宫纤维发育的干细胞的影响，并确定在干细胞水平上的治疗干预是否可以为这种疾病带来更好的管理策略。