MECHANISMS REGULATING UTERINE MORPHOGENESIS

描述：(摘自申请者摘要)人类不孕不育， 妊娠丢失和宫内发育迟缓是主要的公众 健康问题。大量的育龄妇女经历了这些 问题，这可能是由于子宫发育不全、发育不良和/或功能障碍。 长期目标是了解荷尔蒙、细胞和分子 子宫形态发生的调控机制。具体而言，拟议的研究 重点介绍了子宫内膜腺分化的调控机制和 发育或腺生成。子宫腺生成是子宫发育的关键期 在人类胎儿中发生的形态发生，但在之后的新生儿中 在有蹄目动物和啮齿动物中出生。对绵羊和啮齿动物的研究表明 子宫腺体无疑是胚胎存活、生长和发育所必需的。 植入。因此，调控子宫的发育机制的成功 形态发生决定了胚胎的营养潜力和功能能力 成人子宫。我们的研究表明：新生绵羊子宫内膜 腺生成发生在出生后的头八周内，并与 血清催乳素(PRL)和雌二醇17b(E2-17b)水平升高； 新生儿子宫内膜腺的增殖和形态发生活性 子宫表达长短催乳素受体(PRL-R)，胰岛素样生长 因子1受体(IGF1R)和高水平雌激素受体α (er-a)；发育中的腺体周围的基质细胞表达IGF-I， IGF-II和ER-a。IGF1R和短、长PRL-R都能刺激 丝裂原活化蛋白激酶(MAPK)信号转导通路。在其他系统中， 刺激IGF1R可导致非配体依赖的ER-a的激活 方式通过MAPK。我们的中心假设是PRL、E2-17b和IGFS调节 MAPK信号通路和ER-a激活的子宫内膜腺发生 通过配体依赖(E2-17b)和配体非依赖(PRL，IGFS) 机械装置。使用多学科、协作的方法，在体内和 器官培养系统将被用来检验中心假说 以新生绵羊子宫为模型系统。完成这些研究目标 有望极大地促进我们对发展的理解 子宫生物学方面，成人子宫功能的决定因素，并提供 设计临床疗法的基础，以预防、识别和 治疗人类生殖问题，如不孕不育和妊娠丢失 子宫内膜腺发育不全、发育不良或功能障碍。

DESCRIPTION: (Scanned from the applicant's abstract) Human infertility, pregnancy loss and intrauterine growth retardation represent major public health problems. A large number of reproductive age women experience these problems, which may be due to uterine dysgenesis, dysplasia and/or dysfunction. Long-term objectives are to understand the hormonal, cellular and molecular mechanisms regulating uterine morphogenesis. The proposed research specifically focuses on mechanisms regulating endometrial gland differentiation and development or adenogenesis. Adenogenesis is a critical period of uterine morphogenesis that occurs in the fetus in humans, but in the neonate after birth in ungulates and rodents. Studies in sheep and rodents indicate that uterine glands are unequivocally required for conceptus survival, growth and implantation. Thus, success of developmental mechanisms regulating uterine morphogenesis dictates the embryotrophic potential and functional capacity of the adult uterus. Our studies indicate that: neonatal ovine endometrial adenogenesis occurs during the first eight weeks after birth and is associated with increased levels of serum prolactin (PRL) and estradiol-17b (E2-17b); proliferating and morphogenetically active endometrial glands in the neonatal uterus express short and long prolactin receptors (PRL-R), insulin like growth factor one receptors (IGF1R), and high levels of estrogen receptor alpha (ER-a); and stromal cells surrounding the developing glands express IGF-I, IGF-II and ER-a. Both the IGF1R and the short and long PRL-Rs stimulate the mitogen activated protein kinase (MAPK) signaling cascade. In other systems, stimulation of the IGF1R can lead to activation of ER-a in a ligand independent manner by MAPK. Our central hypothesis is that PRL, E2-17b and IGFs regulate endometrial adenogenesis by activation of the MAPK signaling pathway and ER-a through ligand-dependent (E2-17b) and ligand-independent (PRL, IGFs) mechanisms. Using a multidisciplinary, collaborative approach, in vivo and organ culture systems will be used to test the central hypothesis using the neonatal ovine uterus as model system. Accomplishment of these research goals is expected to significantly advance our understanding of the developmental aspects of uterine biology, determinants of adult uterine function, and provide a foundation for the design of clinical therapies to prevent, identify and treat human reproductive problems, such is infertility and pregnancy loss due to endometrial gland dysgenesis, dysplasia or dysfunction.