Functional Role of Wnt11 in Uterine Development and Adult 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成人功能的激素、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。这项建议的重点是Wnt11，这是一种编码一种分泌型糖蛋白的基因，这种糖蛋白在发育中的和成年子宫的上皮中特异表达。Wnt11基因的全基因组破坏会导致围产期死亡。核心假设是Wnt11是出生后子宫发育和成人子宫功能的关键调节因子。为了避免Wnt11缺失小鼠的围产期致死性，我们将使用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Wnt11。孕激素受体仅在出生后的子宫上皮细胞中表达，在M？llerian导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Wnt11在出生后子宫发育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。

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 adult 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 Wnt11, a gene that encodes a secreted glycoprotein that is expressed specifically in the epithelium of the developing and adult uterus. Genome-wide disruption of Wnt11 results in perinatal lethality. The central hypothesis is that Wnt11 is a critical regulator of postnatal uterine development and adult uterine function. In order to circumvent the perinatal lethality of Wnt11-null mice, we will conditionally ablate Wnt11 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 M¿llerian duct differentiation. The conditional mutant mice will be used to test our central hypothesis and understand the biological roles of Wnt11 in postnatal uterine development 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.