Biological Role of Endometrial Glands in Uterine Function

描述（由申请人提供）：不孕症和生育能力低下是人类普遍存在的问题，妊娠丢失是人类妊娠最常见的并发症，妊娠丢失最常发生在妊娠的前两周。我们的长期目标是发现和了解调节子宫妊娠能力的细胞和分子机制，特别关注子宫在囊胚着床中的功能，以便为生育问题的诊断、预防和治疗提供有用的基础信息。当囊胚生长和着床成为可能时，接受性子宫内膜代表了子宫暂时但独特的生理状态。子宫内膜功能不足、容受性和脱个体化对囊胚着床有不利影响，导致妊娠流产。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、子宫内膜脱胞和囊胚着床。这项提议的目标是开始使用缺乏子宫内膜腺（条件Foxa2突变）的小鼠模型来验证这一假设。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去个体化的影响；(2)询问妊娠早期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与缺乏子宫内膜腺的小鼠模型相结合，是一种创新，可能导致鉴定子宫内膜容受性和子宫妊娠能力的新生物标志物。本研究的成功完成将填补我们科学知识的实质性空白，并对子宫和妊娠生物学领域产生重大影响。

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.