Functional Role of Wnt11 in Uterine Development and Adult Function

描述（由申请人提供）： 人类不育和流产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，以便为预防和临床治疗妇女的健康问题提供有用的基本信息。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 11，一种编码分泌糖蛋白的基因，该基因在发育和成年子宫的上皮中特异性表达。Wnt 11的全基因组破坏导致围产期死亡。核心假设是Wnt 11是出生后子宫发育和成年子宫功能的关键调节因子。为了避免Wnt 11基因敲除小鼠的围产期致死性，我们将在出生后使用Cre/LoxP系统和创新的孕酮受体-Cre敲入小鼠模型在子宫上皮中有条件地消融Wnt 11。孕激素受体仅在出生后的子宫上皮中表达，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 11在出生后子宫发育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。

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.