Genetic Regulation of Postnatal Uterine Morphogenesis and Function

描述(由申请人提供)：人类不孕不育和怀孕丢失是妇女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，以便为妇女健康问题的预防和临床治疗提供有用的基础信息。调控子宫形态发生的发育机制的成功在一定程度上决定了成年子宫的胚胎营养潜力和功能能力。在人类，子宫形态发生在胎儿生命后期开始，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，这项拟议的研究将以小鼠为模型系统，研究控制子宫形态发生和功能的基因。这项提案的重点是Wnt7a，这是一种编码一种分泌蛋白的基因，这种蛋白在发育中的和成年子宫的上皮中特异表达。Wnt7a基因的全基因组中断会导致不孕症，原因是子宫和输卵管畸形，这些畸形是由米勒管的发育缺陷引起的，胚胎中的图案和规格。核心假设是Wnt7a是孕期子宫内膜腺形态发生、间质生长和子宫对胚胎容受性的关键调节因子。为了避免Wnt7a在胚胎中缺失时的发育缺陷，我们建议使用Cre/loxP系统和创新的孕激素受体-Cre敲击小鼠模型来有条件地去除出生后子宫上皮中的Wnt7a。孕激素受体仅在出生后的子宫上皮细胞中表达，在苗勒管分化过程中不表达。条件突变小鼠将被用来检验我们的中心假设，并了解Wnt7a在出生后子宫形态发生、子宫内膜再生和成人子宫功能中的生物学作用。这些研究目标的实现有望极大地促进我们对子宫生物学发育方面的了解，以及成人子宫功能的决定因素，并为设计临床治疗方案提供基础，以预防、识别和治疗因子宫发育不全、发育不良或功能障碍而导致的不孕和妊娠丢失等人类生殖问题。这项研究将促进我们对子宫如何发育的理解。子宫发育异常会导致女性不孕不育和妊娠丢失。这项研究将有助于确定与生殖有关的重要基因，并有助于设计临床疗法来预防、识别和治疗女性的生殖问题。

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.