Role of neuroestradiol in regulation of the GnRH surge
神经雌二醇在 GnRH 激增调节中的作用
基本信息
- 批准号:10025846
- 负责人:
- 金额:$ 15.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-15 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AdolescentAdultAgingAndrogensAnimalsApplications GrantsAromataseAromatase InhibitorsAttentionAttenuatedBlood specimenBrainBrain imagingClinical ManagementContraceptive AgentsContraceptive methodsDataDevelopmentEnzymesEstradiolEstradiol BenzoateEstrogensEventFeedbackFemaleFertilityGoalsGonadal Steroid HormonesGonadotropin Hormone Releasing HormoneGonadotropinsGrantHourHypothalamic structureInfertilityInfusion proceduresInjectionsLabelLeadLearningLetrozoleLifeLiquid ChromatographyMeasuresMemoryMenopauseMethodologyMethodsMicrodialysisMonkeysNeuromodulatorNeuronsNeurophysiology - biologic functionNeurosecretory SystemsOvarianOvaryOvulationPerfusionPeriodicityPharmaceutical PreparationsPhysiologyPituitary GlandPituitary GonadotropinsPlayPositron-Emission TomographyPrimatesPubertyPublic HealthRecording of previous eventsRegulationReportingResearchRoleSerumSteroidsSupplementationTestingdesignexperimental studygonad functionin vivoliquid chromatography mass spectrometrymedian eminenceneuron lossnonhuman primatenovel strategiespituitary gonadal axisprepubertyproliferative phase Menstrual cyclereproductive functiontandem mass spectrometrytool
项目摘要
Abstract/Summary
The overall objective of this proposal is to investigate the regulation of gonadotropin-releasing hormone
(GnRH) neurons in the non-human primate. GnRH is released from the hypothalamus and controls
reproductive function through pituitary gonadotropins. The proposed studies are designed to uncover the role
of neuroestradiol in the preovulatory GnRH surge.
It has been shown for many years that circulating E2 released from the ovaries facilitates learning and memory,
protects neurons from neuronal cell death, and regulates reproductive function. However, more recently, a new
concept regarding the role of E2, synthesized and released locally in the brain, as a neuromodulator of neural
functions, has emerged. In fact, our preliminary data indicate that E2 synthesized and released in the stalk-
median eminence (S-ME) of the hypothalamus appears to be necessary for the full gonadotropin surge. That
is, estradiol benzoate (EB)-induced LH surge in ovariectomized (OVX) female monkeys was greatly attenuated
in the presence of the aromatase blocker letrozole. Aromatase is the enzyme necessary for E2 synthesis from
androgens and letrozole is a commonly used competitive blocker for aromatase synthesis. In the proposed
project, we will test the central hypothesis that neuroestradiol, synthesized and released in the hypothalamus
plays a critical role in regulation of preovulatory GnRH release. Three Specific Aims are proposed. Aim 1 will
test the hypothesis that neuroestradiol is an integral part of the estrogen's positive feedback influence on
GnRH release. In Aim 1, we will assess the timing of neuroestradiol increases during the EB-induced LH surge
using letrozole injection as a tool and measuring the changes in LH release. Aim 2 will test the hypothesis that
neuroestradiol increases during the EB-induced GnRH surge are an underling mechanism of the sustained
elevation of GnRH release. In Aim 2 we will measure release of estradiol and GnRH as well as circulating LH
and E2 in EB treated OVX monkeys using a microdialysis method and serial blood sampling followed by
analysis with liquid chromatography-mass spectrometry (LC/MS/MS) and RIA. Aim 3 will test the hypothesis
that aromatase activity in the hypothalamus increases during the preovulatory GnRH surge in vivo. To visualize
aromatase we will use positron emission tomography (PET) scan with 11C-labeled cetrozole as a marker.
The proposed study has great potential to demonstrate that E2 synthesized in the hypothalamus increases
during the preovulatory gonadotropin surge in vivo. In turn, this finding will modify the presently accepted
dogma that E2 of ovarian origin solely controls the hypothalamo-pituitary-gonadal axis.
摘要/概要
本提案的总体目标是研究促性腺激素释放激素的调节
(GnRH)神经元在非人类灵长类动物。促性腺激素释放激素从下丘脑释放,
生殖功能通过垂体促性腺激素。拟议的研究旨在揭示
促性腺激素释放激素高峰中的神经雌二醇。
多年来已经证明,从卵巢释放的循环E2促进学习和记忆,
保护神经元免于神经元细胞死亡,并调节生殖功能。然而,最近,一个新的
关于E2的作用的概念,在大脑中局部合成和释放,作为神经调节剂,
功能,已经出现。实际上,我们的初步数据表明E2在茎中合成和释放-
下丘脑的正中隆起(S-ME)似乎是促性腺激素完全激增所必需的。的
苯甲酸雌二醇(EB)诱导的卵巢切除(OVX)雌猴LH峰显著减弱
在芳香酶阻断剂来曲唑的存在下。芳香化酶是合成E2所必需的酶,
雄激素和来曲唑是芳香酶合成的常用竞争性阻断剂。拟议
项目,我们将测试的中心假设,神经雌二醇,合成和释放在下丘脑
在排卵前GnRH释放的调节中起关键作用。提出了三个具体目标。目标1将
检验神经雌二醇是雌激素正反馈影响的一个组成部分这一假设,
GnRH释放在目标1中,我们将评估EB诱导的LH峰期间神经雌二醇增加的时间
使用来曲唑注射液作为工具,并测量LH释放的变化。目标2将检验以下假设:
在EB诱导的GnRH激增过程中,神经雌二醇增加是持续性GnRH释放的基础机制。
促性腺激素释放激素的升高。在目标2中,我们将测量雌二醇和GnRH的释放以及循环LH
和E2在EB处理的OVX猴中使用微透析方法和连续血液采样,
用液相色谱-质谱法(LC/MS/MS)和RIA分析。目标3将检验假设
下丘脑芳香化酶活性在体内排卵前GnRH激增期间增加。可视化
芳香化酶,我们将使用正电子发射断层扫描(PET),以11 C-标记的西曲唑作为标记物。
这项研究有很大的潜力证明下丘脑合成的E2增加,
在体内排卵前促性腺激素激增期间。反过来,这一发现将修改目前公认的
卵巢起源的E2单独控制下丘脑-垂体-性腺轴的教条。
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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Ei Terasawa-Grilley其他文献
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{{ truncateString('Ei Terasawa-Grilley', 18)}}的其他基金
Role of neuroestradiol in regulation of the GnRH surge
神经雌二醇在 GnRH 激增调节中的作用
- 批准号:
9761548 - 财政年份:2018
- 资助金额:
$ 15.5万 - 项目类别:
Role of neuroestradiol in regulation of the GnRH surge
神经雌二醇在 GnRH 激增调节中的作用
- 批准号:
9597072 - 财政年份:2018
- 资助金额:
$ 15.5万 - 项目类别:
Role of neuroestradiol in regulation of the GnRH surge
神经雌二醇在 GnRH 激增调节中的作用
- 批准号:
10187610 - 财政年份:2018
- 资助金额:
$ 15.5万 - 项目类别:
Role of neuroestradiol in regulation of the GnRH surge
神经雌二醇在 GnRH 激增调节中的作用
- 批准号:
10417073 - 财政年份:2018
- 资助金额:
$ 15.5万 - 项目类别:
Stem Cell-derived GnRH Neurons: Optimization and Characterization
干细胞衍生的 GnRH 神经元:优化和表征
- 批准号:
9331170 - 财政年份:2017
- 资助金额:
$ 15.5万 - 项目类别:
Role of neuroestrogens in control of GnRH release
神经雌激素在控制 GnRH 释放中的作用
- 批准号:
8837042 - 财政年份:2014
- 资助金额:
$ 15.5万 - 项目类别:
Role of neuroestrogens in control of GnRH release
神经雌激素在控制 GnRH 释放中的作用
- 批准号:
8702755 - 财政年份:2014
- 资助金额:
$ 15.5万 - 项目类别:
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