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

• 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
• 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

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.

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。 卵巢衰竭是女孩和年轻女性接受放疗或化疗的常见副作用。鉴于生存率的提高，特别是在乳腺癌患者中，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不良影响的新策略。例如，在小鼠进行放射或化疗之前，卵巢直接暴露于鞘氨醇-I-磷酸(SIP)可维持卵泡及其封闭的卵母细胞的健康和功能不受损害，从而使受精和出生活体后代成为可能。这些研究已经扩展到非人类灵长类动物，在X-射线照射前，在卵巢内注入SIP或SIP激动剂可以保护一组卵泡，这些卵泡可以导致正常的卵巢/月经周期，产生能够植入前胚胎发育的成熟卵母细胞，并且活着的后代没有DNA损伤。SIP激动剂提供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防止卵母细胞死亡。我们正在研究其他类型的卵巢细胞，即围绕卵母细胞和/或卵巢血管系统的卵泡细胞，是否也能幸免于使用SIP激动剂治疗猕猴的辐射毒性效应。从猕猴卵巢分离的腔前卵泡被包裹起来进行三维培养，根据培养时间和生长速度，分泌类固醇和局部非类固醇因子(抗苗勒氏激素[AMH]，血管内皮生长因子[VEGF])。早期胃窦发育与激素和血管内皮生长因子增加有关，但与AMH分泌减少有关。AMH水平与卵母细胞成熟或健康状况无关。因此，卵泡的生长模式，而不是卵母细胞的成熟，可以从培养的头两周的AMH水平来确定。继续努力优化猕猴的卵泡培养系统，该系统可转化为临床使用，用于女性癌症患者的生育保护。