PRE-CLINICAL TRIALS FOR FEMALE FERTILITY PRESERVATION

女性生育力保存的临床前试验

• 批准号: 8357745
• 负责人: Mary B Zelinski
• 金额: $ 3.63万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357745
• 关键词: 2 year old; Adverse effects; Agonist; Apoptotic; Biological Preservation; Cancer Patient; Ceramides; Embryonic Development; Failure; Female; Fertility; Fertilization; Funding; Generations; Genomics; Gonadal structure; Grant; Human; Infertility; Life; Macaca; Macaca mulatta; Mus; National Center for Research Resources; Oocytes; Ovarian; Ovary; Partner in relationship; Primates; Principal Investigator; Puberty; Radiation; Radiation induced damage; Radiation therapy; Research; Research Infrastructure; Resources; Safety; Source; Stress; Technology; United States National Institutes of Health; Validation; cancer therapy; cost; in vivo; irradiation; meetings; neoplastic cell; offspring; preclinical study; prevent; sensor; sphingosine 1-phosphate; success

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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 早期卵巢衰竭和不孕是抗癌治疗众所周知的副作用。保留女性癌症患者生育能力和卵巢功能的尝试收效甚微。 在小鼠中，1-磷酸鞘氨醇 (S1P) 是一种促凋亡应激传感器神经酰胺的代谢产物，可保护卵巢免受体内辐射引起的损伤，保持正常的生育水平，并通过保护卵母细胞免受辐射而孕育后代。 S1P没有显示出跨代基因组损伤的证据。 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尚待确定。 仅将 S1P 递送至卵巢从而阻止 S1P 的全身可用性的技术也需要验证，而 S1P 可能有利于靶向破坏的肿瘤细胞。 具体目标是1）确定S1P是否可以直接注射到恒河猴卵巢中以保护性腺免受放射治疗引起的体内损伤； 2）评估S1P保护的猕猴卵母细胞免受放射治疗的受精和胚胎发生的能力； 3) 评估体内受S1P保护免受放射治疗的猕猴卵母细胞所孕育的后代是否显示出繁殖性基因组损伤的证据。 经 S1P 激动剂治疗并接受卵巢 X 射线照射的雌性，产生了 5 个活的、正常的后代。 它们现在已经1-2岁了，将维持到青春期，然后交配以评估第二代是否没有基因组损伤。 因此，S1P有潜力作为一种安全有效的策略来保护人类卵巢免受抗癌治疗造成的损害，并预防不孕症。