Human infertility, pregnancy loss and intrauterine growth retardation represent major public health problems. A large number of reproductive age women experience these problems, which may be due to uterine dysgenesis, dysplasia and/or dysfunction. Long-term objectives are to understand the hormonal, cellular and molecular mechanisms regulating uterine morphogenesis. The proposed research specifically focuses on mechanisms regulating endometrial gland differentiation and development or adenogenesis. Adenogenesis is a critical period of uterine morphogenesis that occurs in the fetus in humans, but in the neonate after birth in ungulates and rodents. Studies in sheep and rodents indicate that uterine glands are unequivocally required for conceptus survival, growth and implantation. Thus, success of developmental mechanisms regulating uterine morphogenesis dictates the embryotrophic potential and functional capacity of the adult uterus. Our studies indicate that: neonatal ovine endometrial adenogenesis occurs during the first eight weeks after birth and is associated with increased levels of serum prolactin (PRL) and estradiol-17b (E2-17b); proliferating and morphogenetically active endometrial glands in the neonatal uterus express short and long prolactin receptors (PRL-R), insulin like growth factor one receptors (IGF1R), and high levels of estrogen receptor alpha (ER-a); and stromal cells surrounding the developing glands express IGF-I, IGF-II and ER-a. Both the IGF1R and the short and long PRL-Rs stimulate the mitogen activated protein kinase (MAPK) signaling cascade. In other systems, stimulation of the IGF1R can lead to activation of ER-a in a ligand independent manner by MAPK. Our central hypothesis is that PRL, E2-17b and IGFs regulate endometrial adenogenesis by activation of the MAPK signaling pathway and ER-a through ligand-dependent (E2-17b) and ligand-independent (PRL, IGFs) mechanisms. Using a multidisciplinary, collaborative approach, in vivo and organ culture systems will be used to test the central hypothesis using the neonatal ovine uterus as model system. Accomplishment of these research goals is expected to significantly advance our understanding of the developmental aspects of uterine biology, determinants of adult uterine function, and provide a foundation for the design of clinical therapies to prevent, identify and treat human reproductive problems, such is infertility and pregnancy loss due to endometrial gland dysgenesis, dysplasia or dysfunction.
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