Genetic Regulation of Postnatal Uterine Morphogenesis and Function

描述（由申请人提供）：人类不孕不育和妊娠失败是女性的主要公共卫生问题。我们的长期目标是发现和了解调节子宫形态发生和功能的激素、细胞和分子机制，以便为预防和临床治疗女性健康问题提供有用的基础信息。调节子宫形态发生的发育机制的成功部分地决定了胚胎营养潜力和成年子宫的功能能力。在人类中，子宫形态发生开始于胎儿晚期，直到出生后才完成，因此排除了对这一关键过程的研究。因此，拟议的研究将利用小鼠作为模型系统来研究控制子宫形态发生和功能的基因。该提案的重点是Wnt 7a，这是一种编码分泌蛋白的基因，该蛋白在发育和成年子宫的上皮中特异性表达。Wnt 7a的全基因组破坏导致不孕症，这是由于胚胎中苗勒管图案化和特化的发育缺陷引起的子宫和输卵管畸形。中心假设是Wnt 7a是出生后子宫内膜腺形态发生和基质生长以及妊娠期间子宫对胚胎的容受性的关键调节剂。为了规避胚胎中Wnt 7a缺失时的发育缺陷，我们提出使用Cre/LoxP系统和创新的孕酮受体-Cre敲入小鼠模型在出生后有条件地消融子宫上皮中的Wnt 7a。孕激素受体仅在出生后的子宫上皮中表达，而在苗勒管分化期间不表达。条件突变小鼠将用于测试我们的中心假设，并了解Wnt 7a在出生后子宫形态发生，子宫内膜再生和成年子宫功能中的生物学作用。这些研究目标的实现，预计将显着推进我们的子宫生物学的发育方面的理解，成人子宫功能的决定因素，并提供了一个基础的临床治疗设计，以预防，识别和治疗人类生殖问题，如不孕症和妊娠丢失，由于子宫发育不良，发育不良或功能障碍。这项研究将促进我们对子宫发育的理解。子宫发育异常可导致女性不孕和流产。这项研究将有助于确定生殖的重要基因，并有助于设计临床疗法，以预防，识别和治疗妇女的生殖问题。

DESCRIPTION (provided by applicant): Human infertility and pregnancy loss represent major public health problems in women. Our long- range goal is to discover and understand the hormonal, cellular, and molecular mechanisms regulating uterine morphogenesis and function in order to provide fundamental information useful for prevention and clinical treatment of women's health problems. The success of developmental mechanisms regulating uterine morphogenesis dictates, in part, the embryotrophic potential and functional capacity of the adult uterus. In humans, uterine morphogenesis begins late in fetal life and is not completed until after birth, thereby precluding study of this critical process. Therefore, the proposed research will utilize mice as a model system to investigate genes governing uterine morphogenesis and function. The focus of this proposal is on Wnt7a, a gene that encodes a secreted protein that is expressed specifically in the epithelium of the developing and adult uterus. Genome- wide disruption of Wnt7a results in infertility due to uterine and oviductal malformations arising from developmental defects in Mullerian duct patterning and specification in the embryo. The central hypothesis is that Wnt7a is a critical regulator of postnatal endometrial gland morphogenesis and stromal growth and uterine receptivity to the embryo during pregnancy. In order to circumvent the developmental defects when Wnt7a is deleted in the embryo, we propose to conditionally ablate Wnt7a in the epithelium of the uterus after birth using the Cre/LoxP system and the innovative progesterone receptor-Cre knockin mouse model. The progesterone receptor is only expressed in the epithelium of the uterus after birth and is not expressed during Mullerian duct differentiation. The conditional mutant mice will be used to test our central hypothesis and understand the biological roles of Wnt7a in postnatal uterine morphogenesis, endometrial regeneration and adult uterine function. 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 as infertility and pregnancy loss, due to uterine dysgenesis, dysplasia or dysfunction. This research will advance our understanding of the how the uterus develops. Abnormal development of the uterus can cause infertility and pregnancy loss in women. This research will help determine important genes for reproduction and help to design clinical therapies to prevent, identify and treat reproductive problems in women.