AMH AS PREDICTOR OF FOLLICLE FUNCTION DURING ENCAPSULATED 3D CULTURE IN MACAQUES

AMH 作为猕猴封装 3D 培养期间卵泡功能的预测因子

基本信息

批准号：
8357774
负责人：
Mary B Zelinski
金额：
$ 1.82万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8357774
关键词：
3-Dimensional Adverse effects Agonist Antral Biological Preservation Cancer Patient Cell Death Cells Cessation of life Clinical DNA Damage Development Embryonic Development Encapsulated Exposure to Failure Female Fertility Fertilization Funding Grant Growth Health Infusion procedures Life Live Birth Macaca Malignant Neoplasms Mus National Center for Research Resources Oocytes Ovarian Ovary Pathway interactions Pattern Periodicity Prevention Primates Principal Investigator Production Quality of life Radiation Radio Research Research Infrastructure Resources Source Sphingosine Steroids Survival Rate System Toxic effect Translating United States National Institutes of Health Vascular Endothelial Growth Factors Woman cancer therapy cell type chemotherapy cohort cost girls inorganic phosphate intraovarian irradiation malignant breast neoplasm mullerian-inhibiting hormone nonhuman primate novel strategies offspring oocyte maturation preimplantation

项目摘要

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. Ovarian failure is a common side-effect of radiation or chemotherapy treatment in girls and young women. In view of increasing survival rates, especially in breast cancer patients, long-term consequences of cancer treatments with respect to fertility are important considerations for quality of life after cancer. Novel strategies for protecting the ovaries from adverse effects of cancer therapies are currently under development. For example, direct ovarian exposure to sphingosine-I-phosphate (SIP) prior to radio-or chemotherapy in mice maintains the health and function of follicles and their enclosed oocytes from damage such that fertilization and birth of live offspring are possible. These studies have been extended to nonhuman primates wherein intraovarian infusion of SIP or SIP agonist prior to X-irradiation protects a cohort of follicles that leads to normal ovarian/menstrual cyclicity, production of mature oocytes capable of preimplantation embryonic development and live offspring devoid of DNA damage. One mechanism whereby SIP agonists confer ovarian protection involves the prevention of oocyte death by interference in the cell death pathway induced by radiation. We are investigating whether other ovarian cell types, i.e. follicular cells surrounding the oocyte and/or the ovarian vasculature, are also spared from the toxic effects of radiation with SIP agonist treatment in macaques. Preantral follicles isolated from macaque ovaries and encapsulated for 3-dimensional culture secrete steroids and local nonsteroidal factors (anti-Mullerian hormone [AMH], vascular endothelial growth factor [VEGF]) depending on duration and growth rate in culture. Early antral development is associated with increased steroid and VEGF, but decreased AMH, secretion. AMH levels did not correlate with oocyte maturation or health. Thus, the pattern of follicle growth, but not oocyte maturation, can be determined from AMH levels during the first 2 weeks of culture. Efforts continue to optimize a follicle culture system in macaques that can be translated to clinical use for fertility preservation in female cancer patients.

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。卵巢衰竭是女孩和年轻女性放疗或化疗的常见副作用。鉴于生存率不断提高，尤其是乳腺癌患者的生存率，癌症治疗对生育力的长期影响是癌症后生活质量的重要考虑因素。目前正在开发保护卵巢免受癌症治疗副作用的新策略。例如，在小鼠放疗或化疗之前将卵巢直接暴露于磷酸鞘氨醇（SIP）可以维持卵泡及其封闭卵母细胞的健康和功能免受损害，从而使受精和活体后代的出生成为可能。这些研究已扩展到非人类灵长类动物，其中在 X 射线照射之前向卵巢内输注 SIP 或 SIP 激动剂可保护一群卵泡，从而导致正常的卵巢/月经周期、产生能够植入前胚胎发育的成熟卵母细胞和缺乏 DNA 的活后代损害。 SIP 激动剂赋予卵巢保护的一种机制涉及通过干扰辐射诱导的细胞死亡途径来预防卵母细胞死亡。我们正在研究猕猴中其他卵巢细胞类型，即卵母细胞周围的滤泡细胞和/或卵巢脉管系统，是否也能免受 SIP 激动剂治疗的辐射毒性作用。从猕猴卵巢分离并封装用于 3 维培养的腔前卵泡根据培养的持续时间和生长速度分泌类固醇和局部非类固醇因子（抗苗勒氏管激素 [AMH]、血管内皮生长因子 [VEGF]）。早期胃窦发育与类固醇和 VEGF 的增加有关，但 AMH 的分泌减少。 AMH 水平与卵母细胞成熟或健康无关。因此，可以根据培养前 2 周期间的 AMH 水平来确定卵泡生长的模式，但不能确定卵母细胞的成熟。我们继续努力优化猕猴的卵泡培养系统，并将其转化为临床用于女性癌症患者生育力保存的方法。