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.