Biological Role of Endometrial Glands in Uterine Function

描述(申请人提供)：不孕不育和不孕不育是人类普遍存在的问题，而妊娠丢失是人类妊娠最常见的并发症，最常见的丢失发生在怀孕的前两周。我们的长期目标是发现和了解调控子宫受孕能力的细胞和分子机制，特别是子宫对胚泡着床的作用，以便为生育问题的诊断、预防和治疗提供有用的基础信息。接受型子宫内膜代表着一种暂时但独特的子宫生理状态，此时胚泡的生长和着床是可能的。子宫内膜功能、容受性和蜕膜化不足会对胚泡着床产生负面影响，从而导致妊娠损失。我们的中心假设是子宫内膜腺及其分泌物调节子宫内膜容受性、子宫内膜蜕膜化和胚泡着床。这项建议的目标是开始使用缺乏子宫内膜腺的小鼠模型(条件性Foxa2突变)来验证这一假设。具体目的是：(1)确定子宫内膜腺及其分泌物对子宫内膜容受性和间质蜕膜形成的影响；(2)询问早期妊娠的子宫内膜上皮转录组和分泌组。系统生物学方法利用功能基因组学和基于发现的方法，结合缺乏子宫内膜腺的小鼠模型，具有创新性，可能导致识别子宫内膜容受性和子宫妊娠能力的新生物标记物。这项拟议研究的成功完成将填补我们在科学知识方面的重大空白，并影响子宫和怀孕生物学领域。

DESCRIPTION (provided by applicant): Infertility and subfertility are pervasive problems in humans, and pregnancy loss is the most common complication of human gestation, with losses occurring most frequently in the first two weeks of gestation. Our long-range goal is to discover and understand the cellular and molecular mechanisms regulating uterine competency for pregnancy with a specific focus on uterine functions for blastocyst implantation in order to provide fundamental information useful for diagnosis, prevention and treatment of fertility problems. The receptive endometrium represents a temporary, but unique physiological state of the uterus when blastocyst growth and implantation is possible. Inadequate endometrial function, receptivity and decidualization negatively affect blastocyst implantation leading to pregnancy loss. Our central hypothesis is that endometrial glands and their secretions regulate endometrial receptivity, endometrial decidualization and blastocyst implantation. The goal of this proposal is to begin testing that hypothesis using a mouse model that lacks endometrial glands (conditional Foxa2 mutant). Specific aims are to: (1) determine the impact of endometrial glands and their secretions on endometrial receptivity and stromal decidualization; and (2) interrogate the endometrial epithelial transcriptome and secretome of early pregnancy. The systems biology approach, utilizing functional genomics and discovery-based methods in combination with a mouse model lacking endometrial glands, is innovative and could lead to identification of novel biomarkers of endometrial receptivity and uterine competency for pregnancy. Successful completion of the proposed research will fill a substantial gap in our scientific knowledge and impact the fields of uterine and pregnancy biology.