Anti-Mullerian Hormone Actions to Control Primate Folliculogenesis
抗苗勒氏管激素作用控制灵长类动物毛囊发生
基本信息
- 批准号:10293067
- 负责人:
- 金额:$ 67.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-08-13 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:Adenosine TriphosphateAnabolismAntralAwardBirth RateCell CycleCell Cycle ProgressionCell Cycle RegulationCell ProliferationConsumptionCortex of ovaryCreatineCryopreservationDataDevelopmentEmbryoEmbryo TransferEmbryonic DevelopmentEnergy MetabolismEstradiolEventExhibitsFertilizationFertilization in VitroGoalsGonadotropinsGrowing FollicleGrowthHumanHypoxiaHypoxia Inducible FactorIn VitroLive BirthMacacaMacaca mulattaMediatingMenstrual cycleMetabolic PathwayMetabolismMetaphaseModelingMolecularMorphologyOocytesOutcomeOvarianOvarian StimulationsOvarian TissueOvarian tissue cryopreservationOvaryPeptidesPhysiologicalPlayPregnancyPrimatesPrimordial FollicleProcessProductionProteinsProtocols documentationPublishingRecombinantsRegulationReproductive ProcessResearchRoleSupplementationTestingWomanadvanced maternal ageautocrinebaseexperimental studyfemale fertilityfertility improvementfertility preservationfolliculogenesisgranulosa cellimprovedin vivoinfertility treatmentinsightknock-downmetabolomemullerian-inhibiting hormoneneutralizing antibodynonhuman primateoocyte maturationparacrinepreventreproductive functionresponsesuccesstissue culturetranscriptome
项目摘要
PROJECT SUMMARY
Anti-Müllerian hormone (AMH) plays a key role during ovarian follicular development. We have advanced
our understanding of the dynamic expression, direct action, and physiological role of AMH during
folliculogenesis in rhesus macaques since the initial award of the project. Data suggest that AMH is produced
heterogeneously by developing follicles and exhibits stage-dependent regulatory effects by promoting preantral
follicle growth and preventing antral follicle maturation. Stage-specific AMH modulation improves follicle growth
and maturation in vitro to generate competent oocytes. Therefore, further research is warranted to elucidate
the downstream molecular and cellular events regulated by AMH at the specific stages of follicular
development, as well as the potential for modulation of AMH actions to improve ovarian function and female
fertility. Our preliminary studies show that (a) AMH administration in vivo promotes preantral follicle growth,
resulting in the increased number of antral follicles in the ovary; (b) primordial follicle activation and growth to
the preantral stage is achieved by ovarian tissue culture after cryopreservation; and (c) preantral follicles are
maintained in a state of physiological hypoxia. AMH has the potential to regulate cell cycle progression by
limiting actions of hypoxia-inducible factor, and to control cellular energy production by inducing creatine
biosynthesis and metabolism under hypoxia. Thus, studies will be performed to test the hypothesis that stage-
specific modulation of AMH actions facilitates follicular development in vivo and in vitro, which in turn improves
fertility outcomes. Aim 1 will evaluate the impact of AMH priming on ovarian response to gonadotropin
stimulation during IVF (in vitro fertilization). AMH will be administered in vivo in macaques at advanced
reproductive age or with poor response to controlled ovarian stimulation (COS). The COS protocol will then be
performed to evaluate IVF efficacy. Aim 2 will examine the effect of AMH modulation on in vitro maturation of
follicles from cryopreserved macaque and human ovarian tissue. Vitrified-warmed ovarian cortex will be
cultured to induce primordial follicle activation and growth to the preantral stage. Preantral follicles will then be
isolated and cultured with AMH modulation for oocyte maturation. Aim 3 will determine the molecular
mechanisms whereby AMH regulates cell proliferation and energy production during follicular development.
Macaque preantral follicles will be cultured at 5% O2 with AMH supplementation or knockdown. Factors
regulating cell cycle progression and creatine biosynthesis/metabolic pathway components will be analyzed.
The proposed studies will provide important insight into the mechanism of stage-dependent AMH actions
in regulating follicular development and ovarian function using a nonhuman primate model that is an excellent
surrogate for understanding reproductive processes in women. The findings will allow for developing protocols
for optimizing IVF process, advancing options for female fertility preservation, and defining AMH-mediated
regulation of cell cycle and energy metabolism during folliculogenesis.
项目摘要
抗苗勒管激素(AMH)在卵巢卵泡发育过程中起关键作用。我们拥有先进
我们对AMH的动态表达、直接作用和生理作用的理解,
自该项目最初获得批准以来,恒河猴的卵泡发育。数据显示AMH是由
并通过促进窦前卵泡发育表现出阶段依赖性的调节作用
卵泡生长和阻止有腔卵泡成熟。阶段特异性AMH调节促进卵泡生长
并在体外成熟以产生有能力的卵母细胞。因此,需要进一步的研究来阐明
AMH在卵泡特定阶段调控的下游分子和细胞事件
发展,以及调节AMH的作用,以改善卵巢功能和女性的潜力,
生育我们的初步研究表明,(a)AMH体内给药促进腔前卵泡生长,
导致卵巢中有腔卵泡数量增加;(B)原始卵泡活化和生长,
腔前阶段通过冷冻保存后的卵巢组织培养获得;和(c)腔前卵泡
维持在生理缺氧状态。AMH具有通过以下方式调节细胞周期进程的潜力:
限制缺氧诱导因子的作用,并通过诱导肌酸来控制细胞能量产生
缺氧条件下的生物合成和代谢。因此,将进行研究,以检验假设阶段-
AMH作用的特异性调节促进体内和体外卵泡发育,这反过来又改善了
生育结果。目标1将评估AMH引发对卵巢对促性腺激素反应的影响
IVF(体外受精)。AMH将在猕猴体内给药,
育龄或对控制性卵巢刺激(COS)反应差。COS协议将被
以评估IVF的疗效。目的2将研究AMH调节对体外成熟的
冷冻保存猕猴和人类卵巢组织的卵泡。玻璃化加温的卵巢皮质
培养以诱导原始卵泡活化并生长至腔前阶段。腔前卵泡将被
分离并用AMH调节培养用于卵母细胞成熟。目标3将确定分子
AMH调节卵泡发育过程中细胞增殖和能量产生的机制。
猕猴腔前卵泡将在5%O2下培养,并添加AMH或敲除AMH。因素
将分析调节细胞周期进程和肌酸生物合成/代谢途径组分。
这些研究将为了解AMH的阶段依赖性作用机制提供重要线索
在调节卵泡发育和卵巢功能方面,使用非人灵长类动物模型,
来理解女性的生殖过程。研究结果将允许制定协议
用于优化IVF过程,推进女性生育力保存的选择,并定义AMH介导的
调控卵泡发生过程中的细胞周期和能量代谢。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('ADAM J KRIEG', 18)}}的其他基金
Anti-Mullerian Hormone Actions to Control Primate Folliculogenesis
抗苗勒氏管激素作用控制灵长类动物毛囊发生
- 批准号:
10700008 - 财政年份:2015
- 资助金额:
$ 67.54万 - 项目类别:
ANALYSIS OF HISTONE DEMETHYLASE ACTIVITY IN HYPOXIC CANCER CELLS
缺氧癌细胞中组蛋白去甲基酶活性的分析
- 批准号:
8360685 - 财政年份:2011
- 资助金额:
$ 67.54万 - 项目类别:
Mechanisms of transcriptional repression by p53 during hypoxic stress
缺氧应激期间 p53 转录抑制的机制
- 批准号:
7276847 - 财政年份:2007
- 资助金额:
$ 67.54万 - 项目类别:
Mechanisms of transcriptional repression by p53 during hypoxic stress
缺氧应激期间 p53 转录抑制的机制
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7744004 - 财政年份:2007
- 资助金额:
$ 67.54万 - 项目类别:
Mechanisms of transcriptional repression by p53 during hypoxic stress
缺氧应激期间 p53 转录抑制的机制
- 批准号:
7515446 - 财政年份:2007
- 资助金额:
$ 67.54万 - 项目类别:
Functional Analysis of Histone Demethylase Activity in Hypoxic Cancer Cells
缺氧癌细胞中组蛋白去甲基化酶活性的功能分析
- 批准号:
8480350 - 财政年份:
- 资助金额:
$ 67.54万 - 项目类别:
Functional Analysis of Histone Demethylase Activity in Hypoxic Cancer Cells
缺氧癌细胞中组蛋白去甲基化酶活性的功能分析
- 批准号:
8691928 - 财政年份:
- 资助金额:
$ 67.54万 - 项目类别:
Functional Analysis of Histone Demethylase Activity in Hypoxic Cancer Cells
缺氧癌细胞中组蛋白去甲基化酶活性的功能分析
- 批准号:
8922032 - 财政年份:
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$ 67.54万 - 项目类别:
Functional Analysis of Histone Demethylase Activity in Hypoxic Cancer Cells
缺氧癌细胞中组蛋白去甲基化酶活性的功能分析
- 批准号:
8534219 - 财政年份:
- 资助金额:
$ 67.54万 - 项目类别:
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