DESCRIPTION (provided by applicant): Understanding ovarian function in adults is a requirement to maximize female reproductive health, including providing women sufficient options in fertility regulation and maintenance. When ovarian function fails in young adult women, a condition known as premature ovarian failure (POF), their future fertility is at risk. However, most studies that examine how follicle development can be initiated in the ovary do so in neonatal or peri-pubertal females, not adults. Siberian hamsters (Phodopus sungorus) serve as an ideal model for investigating how a non-functional adult mammalian ovary can resume activity, because exposing these hamsters to different photoperiods, the number of hours of light per day, can turn ovarian function "on" or "off". We have shown that exposure of adult Siberian hamsters to long day photoperiod (LD; 16 hours of light per day, 8 hours of dark per day) maintains ovarian function, whereas exposure to inhibitory short day lengths (SD, 8L:16D) for 14 weeks induces ovarian regression. Subsequent transfer of photo-regressed females to LD stimulates ovarian recrudescence, a process that restarts the non-cycling ovaries. Multiple mechanisms regulate these transitions in ovarian function, although how folliculogenesis actually resumes during recrudescence has not been explored. This proposal hypothesizes that signaling factors promoting folliculogenesis are 1) present in Siberian hamster ovaries and regulated by photoperiod, and 2) differentially regulated by non-gonadotropin factors and FSH in regressed and recrudescing ovaries. The aims of this proposal first use a systematic genomic screening of adult ovaries to identify transcripts up- and down- regulated during recrudescence. Next, an in vivo ablation and restoration of FSH during photo-stimulation examines FSH independent factors triggered by photo-stimulation that may restore follicle growth. Finally, an in vitro culture system will be used to expose recrudescing ovaries to inhibitors of key folliculogenic factors (e.g., AMH, IGF-1, KitL, FoxO3, Src), determining individual contributions of these factors to recrudescence. Culture of regressed ovaries with factors known to systemically mediate photoperiodic change (prolactin, thyroid hormone, kisspeptin) will follow, examining non-gonadotropin triggers of ovarian recrudescence to determine if these factors potentially "prime" the regressed ovary for rapid return to function. Importantly, while signaling factors have been broadly assessed during early stages of folliculogenesis, particularly in peri-pubertal females, no studies have done this in adult tissue with a naturally quiescent ovary as it resumes function. Taken together, the work proposed here will provide a better understanding of the how a non-cycling ovary returns to function, and how folliculogenesis is restored in the adult ovary. Our unique model may yield discovery of novel signaling factors critical for restoration of folliculogenesis, particularly at its early stages. This knowledge is fundamental to our understanding of fertility, considering that follicle activation occurs across the reproductive lifespan, not just during ovarian development.

PUBLIC HEALTH RELEVANCE While many studies have investigated the initiation of ovarian function during the normal developmental process in embryos and pre-pubescent females, ovarian function can fail in adults prior to menopause, and follicle growth must restart to restore fertility. Our studies use a unique model that allows us to examine how non-functional ovaries can resume function in adults. Data generated from these experiments may prove beneficial in treating conditions like premature ovarian failure (POF).