Biological Role of Uterine Glands in Pregnancy

不孕不育和流产是影响女性的常见健康疾病。我们的长期研究目标是 确定调节子宫发育、功能和再生的关键生理和遗传途径 以便诊断、治疗和预防妇女的不孕不育和疾病问题。这个应用程序特别是 重点研究子宫内膜腺，它是所有子宫的特征，对怀孕至关重要。 妊娠丢失是人类妊娠最常见的并发症，反复妊娠丢失和不孕 在子宫腺基因敲除动物模型中观察到。先锋转录因子叉头盒A2 (FOXA2)仅在小鼠和人类子宫的腺体中表达，而子宫发育中起着关键作用 与多种疾病(不孕症、子宫腺肌症、子宫内膜异位症、腺癌)有关。 最近的证据有力地支持了这样一种观点，即子宫腺及其产物具有生物学意义 子宫容受性、胚泡/胚胎存活和着床、基质细胞蜕膜形成的作用 这是怀孕建立过程中必不可少的过程。然而，我们对子宫腺和子宫的理解 FOXA2生物学是非常不完整的，特别是在人类身上。在强劲的初步数据指导下，有两个具体目标 提出：(1)FOXA2对子宫生理的调节；(2)子宫腺对间质细胞的影响 蜕膜化。一种结合使用创新小鼠模型的综合系统生物学方法 人类子宫内膜将被用来发现子宫腺体的重要保守功能。建议数 AIMS在概念和技术上都是创新的，它们一起将通过填补 我们在子宫生物学和妊娠丢失方面的基础知识存在很大差距。此应用程序专门针对 目标是美国国立卫生研究院项目公告PA-16-160，题为《美国国立卫生研究院研究项目资助(家长R01)》，重点是 了解特发性不孕症的早期妊娠丢失及其遗传基础是一项重大研究 NICHD生育和不孕处的优先事项。从长远来看，增加对 子宫腺生物学对于诊断、预防和治疗生育和妊娠问题很重要。 也用于器官替代的再生医学疗法和治疗不孕不育的干细胞疗法 以及女性的疾病。

Infertility and pregnancy loss are common health disorders affecting women. Our long-term research goal is to define critical physiological and genetic pathways that regulate uterine development, function and regeneration in order to diagnose, treat, and prevent infertility and disease problems in women. This application is specifically focused on the glands of the endometrium that are characteristic features of all uteri and critical for pregnancy. Pregnancy loss is the most common complication of human gestation, and recurrent pregnancy loss and infertility are observed in uterine gland knockout animal models. The pioneer transcription factor forkhead box A2 (FOXA2) is expressed solely in the glands of the mouse and human uterus, a critical player in uterine development and function, and implicated in a variety of diseases (infertility, adenomyosis, endometriosis, adenocarcinoma). Recent evidence strongly supports the idea that uterine glands and, by inference, their products have biological roles in uterine receptivity, blastocyst/conceptus survival and implantation, and stromal cell decidualization, which are essential processes in pregnancy establishment. However, our understanding of uterine gland and FOXA2 biology is very incomplete, particular in humans. Guided by strong preliminary data, two specific aims are proposed: (1) FOXA2 regulation of uterine physiology; and (2) impact of uterine glands on stromal cell decidualization. An integrative systems biology approach employing a combination of innovative mouse models and human endometrium will be used to discover important conserved functions of uterine glands. The proposed aims are conceptually and technically innovative and together will have a broad impact on the field by filling a substantial gap in our fundamental knowledge of uterine biology and pregnancy loss. This application specifically targets NIH program announcement PA-16-160 entitled “NIH Research Project Grant (Parent R01)” and focuses on understanding early pregnancy loss and genetic basis of idiopathic female infertility, which is a major research priority of the Fertility and Infertility Branch of the NICHD. In the long term, an increased understanding of uterine gland biology is important for diagnosis, prevention, and treatment of fertility and pregnancy problems and also for regenerative medicine therapies aimed at organ replacement and stem cell therapies to treat infertility and disease in women.