Progesterone signaling in oviductal ciliated cells and reproductive longevity

Reproductive aging has long been attributed primarily to declining ovarian function. However, increasing clinical evidence reveals that many individuals experience early fertility loss despite normal ovarian reserve and regular cycles, suggesting that other tissues critical to reproductive success may undergo aging-related dysfunction. Among these, the oviduct (fallopian tube in humans) is essential for early reproductive events such as oocyte pickup, fertilization, and embryo transport, yet remains poorly understood in the context of reproductive aging. This proposal investigates the novel hypothesis that progesterone receptor (PGR) signaling in oviductal ciliated epithelial cells preserves epithelial health and delays reproductive senescence. This work addresses a critical gap in knowledge: how hormonal signaling in extra-ovarian tissues contributes to fertility maintenance across the lifespan. Our preliminary data reveal that conditional deletion of PGR in oviductal ciliated cells results in progressive infertility beginning in mid-reproductive life, despite normal early fecundity. These findings uncover a previously unrecognized role for progesterone in maintaining the epithelial integrity of the oviduct. The proposed research will define how this signaling axis supports long-term reproductive capacity, offering new insight into unexplained infertility and age-associated reproductive decline. In Aim 1, we will determine how loss of PGR in ciliated epithelial cells impairs epithelial function and reproductive longevity by analyzing ciliary beat frequency, particle tracking, epithelial morphology, and in vivo oocyte pickup capacity. In Aim 2, we will define the molecular mechanisms by which PGR maintains ciliated epithelial cell identity and homeostasis, using single- cell RNA sequencing and transcriptional profiling to uncover progesterone-regulated pathways involved in ciliogenesis, anti-senescence, and epithelial maintenance. By integrating cell-type–specific genetic models, advanced imaging, and transcriptomics, this project will uncover a fundamental new mechanism of reproductive aging. The findings are expected to transform our understanding of hormone-regulated epithelial health and inform strategies to preserve fertility across the reproductive lifespan. Project Number: 1R03HD121464-01 | Fiscal Year: 2026 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Wipawee Winuthayanon | Institution: UNIVERSITY OF MISSOURI-COLUMBIA, COLUMBIA, MO | Award Amount: $153,675 | Activity Code: R03 | Study Section: Special Emphasis Panel[ZRG1 EMS-C (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11332046