PRE-CLINICAL TRIALS FOR FEMALE FERTILITY PRESERVATION

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目的总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 早期卵巢衰竭和不孕症是众所周知的抗癌治疗的副作用。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），促凋亡应激传感器神经酰胺的代谢产物，保护卵巢免受体内辐射诱导的损伤，保持正常水平的生育能力，用S1 P保护免受辐射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。 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，也需要验证。 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。 五个活的，正常的后代来自S1 P激动剂治疗的女性接受卵巢X射线照射。 它们现在已经1-2岁了，将一直维持到青春期，然后交配，以评估第二代是否没有基因组损伤。 因此，S1 P有可能作为一种安全有效的策略，用于保护人类卵巢免受抗癌治疗引起的损伤，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. 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.