PRE-CLINICAL TRIALS FOR FEMALE FERTILITY PRESERVATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 早期卵巢衰竭和不孕不育是众所周知的抗癌治疗的副作用。这些治疗对卵巢等非靶标组织的长期影响是巨大的。保留女性癌症患者生育力和卵巢功能的尝试收效甚微。在小鼠身上，促凋亡应激感受器神经酰胺的代谢物-1-磷酸鞘氨醇(S1P)， 在体内完全保护卵巢免受辐射损伤。在体内，S1P在受辐射的雌性小鼠中保持了正常的生育水平，用S1P保护的卵母细胞受孕的后代没有显示出跨代基因组损伤的证据。因此，可以开发基于S1P的策略来对抗不孕症和卵巢衰竭。S1P在接受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需要确定。仅将S1P输送到卵巢的技术，从而防止S1P在全身获得，这可能有利于目标为破坏的肿瘤细胞，还 需要验证。其具体目的是：1)确定S1P是否可以直接注射到恒河猴卵巢以保护性腺免受体内放射损伤；2)评估S1P保护的猕猴卵母细胞受精和胚胎发生的能力；3)评估体内S1P保护的猕猴卵母细胞受孕的后代是否显示出繁殖的基因组损伤的证据。长期目标是开发安全有效的策略，保护体内的人类卵巢免受抗癌治疗引起的副作用损害，并预防不孕不育。

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.