Regulation of Folliculogenesis During Ovarian Recrudescence

 描述（由申请人提供）：了解成年人的卵巢功能是最大限度地提高女性生殖健康的要求，包括为女性提供足够的生育调节和维持选择。当年轻成年女性的卵巢功能衰竭时，即所谓的卵巢过早衰竭（POF），她们未来的生育能力就会面临风险。然而，大多数研究卵泡发育如何在卵巢中启动的研究都是在新生儿或青春期女性中进行的，而不是成年人。西伯利亚仓鼠（Phodopus sungorus）是研究无功能成年哺乳动物卵巢如何恢复活动的理想模型，因为将这些仓鼠暴露于不同的光周期，每天光照的小时数，可以打开或关闭卵巢功能。我们已经表明，暴露于成年西伯利亚仓鼠长日照光周期（LD;每天16小时的光，每天8小时的黑暗）保持卵巢功能，而暴露于抑制性短日照长度（SD，8L：16 D）14周诱导卵巢退化。随后转移的光退化的女性到LD刺激卵巢复发，一个重新启动非周期卵巢的过程。多种机制调节卵巢功能的这些转变，尽管在复发期间卵泡发生实际上如何恢复尚未探讨。该提议假设促进卵泡发生的信号传导因子1）存在于西伯利亚仓鼠卵巢中并受光周期调节，2）在退化和复发卵巢中受非促性腺激素因子和FSH的差异调节。该提案的目的首先使用成年卵巢的系统基因组筛选来鉴定在复发期间上调和下调的转录物。接下来，在光刺激期间FSH的体内消融和恢复检查由光刺激触发的FSH独立因子，其可以恢复卵泡生长。最后，在 体外培养系统将用于将复发的卵巢暴露于关键卵泡生成因子的抑制剂（例如，AMH，IGF-1，KitL，FoxO 3，Src），确定这些因素对复发的个体贡献。将用已知系统介导光周期变化的因子（催乳素、甲状腺激素、kisspeptin）培养退化卵巢，检查卵巢复发的非促性腺激素触发因素，以确定这些因子是否潜在地“准备”退化卵巢快速恢复功能。重要的是，虽然信号因子在卵泡发生的早期阶段得到了广泛的评估，特别是在青春期前后的女性中，但还没有研究在卵巢恢复功能时自然静止的成年组织中进行过这一研究。总之，本文提出的工作将更好地了解非周期性卵巢如何恢复功能，以及卵泡发生如何在成年卵巢中恢复。我们独特的模型可能会发现新的信号传导因子的关键恢复卵泡，特别是在其早期阶段。这些知识对于 我们对生育的理解，考虑到卵泡激活发生在整个生殖过程中， 寿命，而不仅仅是在卵巢发育期间。

 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.