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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 早期的卵巢衰竭和不育是抗癌治疗的众所周知的副作用。女性癌症患者的生育能力和卵巢功能的尝试几乎没有成功。 在小鼠中，鞘氨醇1-磷酸（S1P）是一种促凋亡应力传感器神经酰胺的代谢产物，可保护卵巢免受体内辐射诱导的损害，可保留正常的生育能力，并且在S1P受到辐射构成的卵巢造成的卵巢损害中，均未表现出跨性别损害的卵母细胞。 需要确定S1P对维护卵巢功能和暴露于抗癌治疗的灵长类动物的生育能力的安全性和功效。 仅向卵巢传递S1P的技术，从而防止S1P的系统性可用性，从而使目标造成破坏的肿瘤细胞受益，也需要验证。 具体目的是1）确定是否可以直接将S1P施用到恒河猴卵巢中，以保护性腺免受放疗诱导的体内损伤； 2）评估S1P免受放射疗法保护的猕猴的能力； 3）评估S1P在体内保护免于放射疗法的猕猴的后代是否显示出基因组损伤的证据。 五个现场直播的正常后代源自接受卵巢X-辐照的S1P激动剂治疗的女性。 它们现在已经1-2岁了，将维持直到青春期，然后交配以评估第二代没有基因组损害。 因此，S1P具有保护人类卵巢免受抗癌疗法损害并防止不孕症的损害的安全有效策略的潜力。