Anti-Mullerian hormone actions to control primate folliculogenesis

抗缪勒氏管激素作用控制灵长类动物卵泡发生

• 批准号: 9274843
• 负责人: Jing Xu
• 金额: $ 38.46万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-13 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9274843
• 关键词: Ablation; Address; Adult; Aftercare; Antibodies; Antral; Aromatase; Assisted Reproductive Technology; Biological Assay; Biological Markers; Clinical; Clinical assessments; Competence; Complex; Contraceptive methods; Critical Pathways; Data; Development; Dimensions; Embryonic Development; Endocrine; Female; Fertility; Fertilization; Fertilization in Vitro; Follicle Stimulating Hormone; Gene Expression; Genes; Goals; Growing Follicle; Growth; Histology; Hormones; Human; In Situ; In Vitro; Individual; Infertility; Infusion procedures; Knowledge; LH Receptors; Luteal Phase; Macaca; Macaca mulatta; Malignant Neoplasms; Massive Parallel Sequencing; Menstrual cycle; Messenger RNA; Modeling; Monitor; Monkeys; Morphology; Mus; Oocytes; Ovarian; Ovarian Follicle; Ovary; Pathway interactions; Pattern; Physiological; Play; Polycystic Ovary Syndrome; Primates; Process; Production; Proteins; Regulation; Research; Resource Sharing; Rodent; Role; Serum; Signal Pathway; Steroid biosynthesis; Steroids; Techniques; Testing; Translating; Vascular Endothelial Growth Factors; Woman; autocrine; endometriosis; experimental study; folliculogenesis; genome-wide; granulosa cell; improved; in vivo; insight; intraovarian; mullerian-inhibiting hormone; nonhuman primate; novel; oocyte maturation; paracrine; preimplantation; prevent; primary ovarian insufficiency; proliferative phase Menstrual cycle; public health relevance; receptor expression; reproductive senescence; transcriptome; translational study

 DESCRIPTION (provided by applicant): The goal of this research is to understand the mechanisms whereby anti-Müllerian hormone (AMH) either directly, or indirectly via other locally synthesized factors, regulates preantral follicle growth and antral follicle maturation in the stag-dependent manner in primates during the menstrual cycle. Increasing evidence suggests that AMH alters preantral follicle growth; and the discovery that AMH reduces aromatase and luteinizing hormone receptor expression in cultured granulosa cells adds another dimension to possible AMH actions in antral follicles. Likewise, the PI's evidence that AMH is heterogeneously and dynamically expressed in the macaque follicles reinforces the concept of stage-dependent AMH actions during primate folliculogeneisis. Finally, the recent "in vitro follicl maturation" (IFM) technique provides a feasible model for manipulative studies to unravel local factors and signaling pathways that are critical to the follicular development and oocyte maturation in the primate ovary. Therefore, translational studies are proposed in the adult, female rhesus monkeys, to test the hypotheses that: (Aim 1) AMH promotes preantral follicle growth, but inhibits antral follicle maturation in vitro and (Aim 2) AMH promotes preantral-to-antral follicle growth, but prevents further maturation and selection of the dominant follicle durig the follicular phase of the menstrual cycle in vivo. AMH addition (recombinant human AMH protein) and ablation (anti-human AMH antibody) experiments will be conducted through IFM in vitro and intraovarian infusion in vivo. Follicular morphology and histology, as well as function i steroidogenesis and local factor production, oocyte maturation and competence in fertilization and preimplantation development, plus genome-wide mRNA levels and selected AMH-regulated genes (Aim 3) will be analyzed with the assistance of the Assisted Reproductive Technologies Support Core and Massively Parallel Sequencing Shared Resource. AMH will also be examined as a noninvasive biomarker for further follicle growth and oocyte maturation during IFM. Finally, data generated from the nonhuman primate research will be applied to human IFM with the hypothesis that AMH manipulation improves the coordinated development and maturation of human follicles and their enclosed oocytes (Aim 4). These experiments will provide valuable information on the heterogeneous expression and stage- dependent actions of AMH in ovarian follicles, as well as mechanisms of AMH controlling follicular development, in primates. New insight will emerge on the potential of AMH to serve as a biomarker for follicle growth and oocyte competence during IFM. Emerging concepts should refine clinical paradigms, e.g., local AMH action or value as a biomarker of ovarian reserve in infertility, including primary ovarian insufficiency, polycystic ovarian syndrome, endometriosis, in vitro fertilization, reproductive aging and cancer.

 描述（由申请人提供）：本研究的目的是了解抗苗勒氏管激素（AMH）直接或通过其他局部合成因子间接调节窦前卵泡生长和窦卵泡成熟的机制。越来越多的证据表明，AMH 会改变窦前卵泡的生长，并且发现 AMH 芳香酶和黄体生成素在灵长类动物中会减少。培养的颗粒细胞中的激素受体表达为窦卵泡中可能的 AMH 作用增加了另一个维度。同样，PI 的证据表明 AMH 在猕猴卵泡中呈异质和动态表达，这强化了灵长类卵泡发生过程中 AMH 作用的阶段依赖性的概念。最近的“体外卵泡成熟”（IFM）技术为操作性研究提供了一个可行的模型，以阐明关键的局部因素和信号通路因此，建议在成年雌性恒河猴中进行转化研究，以检验以下假设：（目标 1）AMH 促进窦前卵泡生长，但在体外抑制窦前卵泡成熟。 （目标 2）AMH 促进窦前至窦卵泡生长，但阻止卵泡发育过程中优势卵泡的进一步成熟和选择体内AMH添加（重组人AMH蛋白）和消融（抗人AMH抗体）实验将通过体外IFM和体内卵巢内输注进行，以及类固醇生成功能。和局部因子生产、卵母细胞成熟和受精和植入前发育的能力，以及全基因组 mRNA 水平和选定的 AMH 调节基因（目标 3）将在以下方面进行分析：辅助生殖技术支持核心和大规模并行测序共享资源也将作为 IFM 期间卵泡进一步生长和卵母细胞成熟的非侵入性生物标志物进行检查。 AMH 操作可改善人类卵泡及其封闭卵母细胞的协调发育和成熟（目标 4）。这些实验将为 AMH 的异质表达和阶段依赖性作用提供有价值的信息。关于 AMH 在 IFM 期间作为卵泡生长和卵母细胞能力的生物标志物的潜力，将会出现新的见解，例如局部监测。 AMH 作为卵巢储备功能生物标志物在不孕症（包括原发性卵巢功能不全、多囊卵巢综合征、子宫内膜异位症）中的作用或价值，体外受精、生殖衰老和癌症。