PRE-CLINICAL TRIALS FOR FEMALE FERTILITY PRESERVATION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 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。保留女性癌症患者生育力和卵巢功能的尝试收效甚微。在小鼠中，1-磷酸鞘氨醇(S1P)是促凋亡应激传感器神经酰胺的代谢物，在体内保护卵巢免受辐射诱导的损伤，保持正常的生育水平，并且用S1P保护的卵母细胞受孕的后代没有证据表明跨代基因组损伤。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，从而阻止S1P在全身可用，从而使目标为破坏的肿瘤细胞受益的技术也需要验证。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。五个活的、正常的后代来自接受S1P激动剂治疗的接受卵巢X-射线照射的雌性动物。它们现在1-2岁，将一直保持到青春期，然后进行交配，以评估第二代是否没有基因组损伤。因此，S1P有可能成为一种安全有效的策略来保护人类卵巢免受抗癌治疗所造成的损害，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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Early ovarian failure and infertility are well-known side effects of anti-cancer treatments. 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, protects the ovaries from radiation-induced damage in vivo, preserves a normal level of fertility, and offspring conceived with oocytes protected from radiation by S1P show no evidence of transgenerational genomic damage. 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. Five live, normal offspring were derived from S1P agonist-treated females who received ovarian X-irradiation. They are now 1-2 years old and will be maintained until puberty and then mated to assess whether the second generation is free from genomic damage. Thus, S1P has potential as a safe and effective strategy for protecting human ovaries from the damage caused by anti-cancer therapies, and prevent infertility.