Biological Role of Uterine Glands in Pregnancy

不孕症和流产是影响妇女的常见健康疾病。我们的长期研究目标是 定义调节子宫发育、功能和再生的关键生理和遗传途径 以诊断、治疗和预防妇女的不孕症和疾病问题。该应用程序具体为 重点是子宫内膜的腺体，这是所有子宫的特征，对怀孕至关重要。 妊娠丢失是人类妊娠期最常见的并发症，反复妊娠丢失和不孕症 在子宫腺敲除动物模型中观察到。先锋转录因子叉头盒A2 FOXA 2仅在小鼠和人类子宫的腺体中表达，这是子宫发育的关键因素。 和功能，并涉及各种疾病（不孕症，子宫腺肌病，子宫内膜异位症，腺癌）。 最近的证据有力地支持了子宫腺及其产物具有生物学活性的观点。 在子宫容受性、胚泡/孕体存活和植入以及基质细胞蜕膜化中的作用， 这是怀孕的基本过程。然而，我们对子宫腺和 FOXA 2生物学非常不完整，特别是在人类中。在强有力的初步数据的指导下，两个具体目标 提出：（1）FOXA 2调节子宫生理;（2）子宫腺对基质细胞的影响 蜕膜化采用创新小鼠模型组合的综合系统生物学方法 和人子宫内膜将用于发现子宫腺的重要保守功能。拟议 这些目标在概念和技术上都是创新的，它们将共同对该领域产生广泛影响， 我们在子宫生物学和妊娠丢失的基础知识方面存在巨大差距。本申请具体 目标是NIH项目公告PA-16-160，标题为“NIH研究项目资助（父R 01）”，重点是 了解早期妊娠丢失和特发性女性不孕症的遗传基础，这是一个重大的研究 这是国家排雷中心生育和不育分支的优先事项。从长远来看， 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 也用于旨在治疗不孕症的器官置换和干细胞疗法的再生医学疗法 和妇女的疾病。

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.