PROJECT SUMMARY/ABSTRACT
Approximately 14% of infertility cases that undergo assisted reproductive technologies (ART) are due to
Fallopian tube dysfunction. In 2015 alone, over 230,000 ART cycles were performed in the U.S, yet, less than
30% of those cycles resulted in pregnancy. Moreover, the incidence of epigenetic disorders is increased in in
vitro-conceived embryos. A major contributing factor to the poor success and inherent problems associated with
ART is our lack of understanding of the nature of the oviductal environment. Attempts to improve culture media
by mimicking the oviductal environment, however, have been limited by our lack of understanding of the optimal
microenvironment provided by the oviduct and how it changes during the course of preimplantation embryo
development. Therefore, our long-term goal is to identify the key factors produced by each epithelial cell type
that are crucial for sperm migration, fertilization, embryo development, and embryo transport. It has been
established that ovarian-derived steroid hormones, estrogen (E2) and progesterone (P4), modulate the function
of epithelial cell lining of the oviduct. However, how steroids modulate the function of these epithelial cell
populations that are tailored for each specific stage during pregnancy establishment is undefined. As such, in
this study, we will develop a spatiotemporal map of steroid actions and their effect on oviductal epithelial cells
during the course of sperm/embryo transport and embryo development. Specifically, using mouse models, we
will determine how E2 and P4 mediate distinct populations of epithelial cells of the oviduct to create an appropriate
milieu that changes at different points in time during the course of pre-implantation embryo development. Our
central hypothesis is that fine-tuning of the oviductal epithelium through the actions of E2 and P4 allows the
oviduct to create a malleable environment that supports fertilization and responds to the changing metabolic
needs of developing embryos. We propose to: determine the roles of 1) E2 and 2) P4 signals through their
classical nuclear receptor either in the secretory or the ciliated epithelial cell of the oviduct during the sperm
migration, the time of fertilization, pre-implantation embryo development, and embryo transport. Also, 3) gene
expression profile corresponding to E2 and P4 action in epithelial cell populations at different regions of the
oviduct and at distinct stages will be defined at a single cell resolution using mouse models. The successful
completion of these aims will fill fundamental gaps in knowledge for two main reasons. First, the information will
provide novel insight into the molecular mechanisms driving oviductal functions. Second, understanding which
cell populations function during each stages of sperm/embryo transport and embryo development will generate
much needed information to optimize culture conditions in an ART setting.