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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 卵巢功能衰竭是女孩和年轻女性放疗或化疗的常见副作用。鉴于生存率的提高，特别是在乳腺癌患者中，癌症治疗对生育能力的长期影响是癌症后生活质量的重要考虑因素。 保护卵巢免受癌症治疗不良影响的新策略目前正在开发中。 例如，在小鼠中，在放疗或化疗之前将卵巢直接暴露于鞘氨醇-1-磷酸（S1 P），可维持卵泡及其封闭的卵母细胞的健康和功能免受损害，从而使受精和活后代的出生成为可能。 这些研究已经扩展到非人灵长类动物，其中在X射线照射前卵巢内输注S1 P或S1 P激动剂保护一组卵泡，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没有DNA损伤的活后代。 S1 P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。 我们正在研究其他卵巢细胞类型，即卵母细胞和/或卵巢血管周围的卵泡细胞，是否也免于S1 P激动剂治疗猕猴辐射的毒性作用。从猕猴卵巢中分离并封装用于三维培养的腔前卵泡分泌类固醇和局部非类固醇因子（抗苗勒管激素[AMH]，血管内皮生长因子[VEGF]），这取决于培养的持续时间和生长速率。 早期胃窦发育与类固醇和VEGF增加有关，但AMH分泌减少。AMH水平与卵母细胞成熟或健康无关。 因此，卵泡生长的模式，而不是卵母细胞成熟，可以确定从AMH水平在培养的前2周。 继续努力优化猕猴中的卵泡培养系统，该系统可以转化为临床应用，用于女性癌症患者的生育力保护。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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-1-phosphate (S1P) 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 S1P or S1P 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 S1P 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 S1P 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.