MECHANISMS REGULATING UTERINE MORPHOGENESIS

描述：（扫描自申请人摘要）人类不育， 流产和胎儿宫内发育迟缓是主要的公众问题， 健康问题大量的育龄妇女经历这些 问题，这可能是由于子宫发育不良，发育不良和/或功能障碍。 长期目标是了解激素，细胞和分子 调节子宫形态发生的机制。具体而言，研究建议 着重于调节子宫内膜腺体分化的机制， 发育或腺生成。腺泡形成是子宫发育的关键时期 在人类胎儿中发生的形态发生，但在新生儿中， 在有蹄类动物和啮齿类动物中出生。对绵羊和啮齿动物的研究表明， 子宫腺是胎儿存活、生长和发育所必需的， 置入因此，成功的发育机制调节子宫 形态发生决定了胚胎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前八周， 血清催乳素（PRL）和雌二醇-17 b（E2- 17 b）水平升高; 新生儿子宫内膜腺体增生和形态发生活跃 子宫表达短和长催乳素受体（PRL-R），胰岛素样生长 第一因子受体（IGF 1 R）和高水平的雌激素受体α （ER-α）;并且发育中的腺体周围的基质细胞表达IGF-I， IGF-II和ER-a。IGF 1 R和短和长PRL-R都刺激胰岛素抵抗。 丝裂原活化蛋白激酶（MAPK）信号级联。在其他系统中， IGF 1 R的刺激可导致ER-α以配体非依赖性方式活化， MAPK的方式。我们的中心假设是，PRL，E2- 17 b和IGFs调节 通过MAPK信号通路和ER-α的激活的子宫内膜腺样变 通过配体依赖性（E2- 17 b）和配体非依赖性（PRL，IGFs） 机制等采用多学科协作方法，在体内和 器官培养系统将被用来测试中心假设， 新生绵羊子宫作为模型系统。实现这些研究目标 预计将大大推进我们对发展的理解 子宫生物学方面，成年子宫功能的决定因素，并提供 临床治疗设计的基础，以预防，识别和 治疗人类生殖问题，如不孕症和妊娠损失， 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.