PRE-CLINICAL TRIALS FOR FEMALE FERTILITY PRESERVATION

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 早期卵巢衰竭和不孕症是众所周知的抗癌治疗的副作用。这些治疗对非靶组织（如卵巢）的长期影响是巨大的。 试图保留女性癌症患者的生育能力和卵巢功能，但收效甚微。 在小鼠中，鞘氨醇-1-磷酸（S1 P），一种促凋亡应激传感器神经酰胺的代谢物， 完全保护卵巢免受体内辐射诱导的损伤。 在体内，S1 P在受辐射的雌性小鼠中保持正常水平的生育力，并且用S1 P保护免受辐射的卵母细胞受孕的后代没有表现出跨代基因组损伤的证据。 因此，可以开发基于S1 P的策略来对抗不孕症和卵巢衰竭。 需要确定S1 P在暴露于抗癌治疗的灵长类动物中保护卵巢功能和生育能力的安全性和有效性。 将S1 P仅递送到卵巢的技术，从而防止S1 P的全身可用性，这可能有利于靶向破坏的肿瘤细胞， 需要验证。 具体目的是：1）确定S1 P是否可以直接给予恒河猴卵巢，以保护性腺免受放射治疗诱导的体内损伤; 2）评价S1 P保护免受放射治疗的猕猴卵母细胞的受精和胚胎发生能力; 3）评估由S1 P保护免受放射治疗的猕猴卵母细胞体内受孕的后代是否显示出繁殖性基因组损伤的证据。 长期目标是开发安全有效的策略，以保护人体卵巢免受抗癌治疗引起的副作用损伤，并预防不孕症。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Early ovarian failure and infertility are well-known side effects of anti-cancer treatments. The long-term consequences of these treatments on non-target tissues, such as the ovaries are substantial. Attempts to preserve fertility and ovarian function in female cancer patients have met with little success. In mice, sphingosine-1-phosphate (S1P), a metabolite of the pro-apoptotic stress sensor ceramide, completely protects the ovaries from radiation-induced damage in vivo. In vivo, S1P preserves a normal level of fertility in irradiated female mice, and offspring conceived with oocytes protected from radiation by S1P show no evidence of transgenerational genomic damage. Thus, S1P-based strategies could be developed to combat infertility and ovarian failure. The safety and efficacy of S1P for preserving ovarian function and fertility in primates exposed to anti-cancer treatments needs to be established. Technologies to deliver S1P only to the ovaries, thereby preventing systemic availability of S1P that could benefit the tumor cells targeted for destruction, also requires validation. The specific aims are 1) to determine if S1P can be administered directly into the rhesus monkey ovary to protect the gonads from radiotherapy-induced damage in vivo; 2) to evaluate the competency of macaque oocytes protected from radiotherapy by S1P for fertilization and embryogenesis; and 3) to assess if offspring conceived from macaque oocytes protected from radiotherapy by S1P in vivo show evidence of propagated genomic damage. The long-term goal is to develop safe and effective strategies for protecting human ovaries in vivo from the side-effect damage caused by anti-cancer therapies, and prevent infertility.