Regulation of gonadotropin secretion during undernutrition by a brainstem-hypothalamic neural pathway
Regulation of gonadotropin secretion during undernutrition by a brainstem-hypothalamic neural pathway
批准号:
10488654
负责人:
KELLIE Breen Church
金额:
$52.77万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-09-30 至 2025-08-31
关键词:
AblationAcuteAmenorrheaAnatomyAnimal ModelAntimetabolitesBrain StemCatecholaminesCellsChronicCorticotropin-Releasing Hormone ReceptorsCouplingDataDeoxyglucoseDevelopmentDiseaseEquilibriumEstradiolEstrusFOS geneFemaleFertilityFoundationsFunctional disorderGNRH1 geneGenerationsGeneticGlucoseGoalsGonadotropin Hormone Releasing HormoneGonadotropinsHormone secretionHypothalamic structureImpairmentInfertilityKISS1 geneKnock-outKnowledgeLuteinizing HormoneMalnutritionMediatingMediator of activation proteinMenstruation DisturbancesMetabolicMetabolic ControlMetabolic stressMethodsMolecularMusNeural PathwaysNeuronsNeuropeptidesNeurosecretory SystemsNorepinephrineOvarianOvarian CyclesPathway interactionsPeriodicityPharmacologyPhysiologic pulsePhysiologicalPopulationProcessProductionRegulationReproductionResearchResearch PersonnelRoleSignal TransductionStressTalentsTestingTransgenic MiceTransgenic OrganismsWomanWorkanovulatory disorderantagonistbiological adaptation to stressdesigner receptors exclusively activated by designer drugsenergy balancefunctional hypothalamic amenorrheaknock-downneuromechanismnovelparaventricular nucleuspreventreceptorrelating to nervous systemreproductivereproductive functionresponsetoolurocortin
中文摘要
项目概要/摘要
这项研究的总体目标是了解压力如何破坏卵巢周期。长期营养不足
是一种代谢压力,损害跨物种的繁殖,在女性中与
功能性下丘脑性闭经的发展,一种不充分的
促性腺激素分泌虽然能量平衡与生殖能力的紧密耦合在
卵巢周期功能障碍的神经内分泌位点和分子机制
对营养不良的认识仍然很少。在女性中,排卵周期依赖于两个
下丘脑内协调促性腺激素释放的kisspeptin(Kiss 1)神经元群
促性腺激素(GnRH)和促黄体生成激素(LH)脉冲以及排卵前GnRH/LH峰的产生。
弓形Kiss 1(ARCKiss 1)对LH脉冲的控制或前腹侧脑室周围Kiss 1的破坏
(AVPVKiss 1)控制LH峰预计会损害女性的卵巢周期性。我们的初步
研究表明,慢性营养不良通过以下途径迅速破坏雌性小鼠的卵巢周期性:
LH脉冲分泌和LH峰均受损。我们表明,这些抑制作用,
通过激活脑干A2 NE神经元或通过中枢给予尿皮质素来重现卵巢周期
2(UCN 2),一种特异性激活促肾上腺皮质激素释放激素受体2(CRHR 2)的神经肽。我们
Kiss 1细胞中CRHR 2的拮抗作用或CRHR 2的敲低降低了Kiss 1细胞的生殖能力,
对营养不足或A2 NE激活的反应抑制提供了测试该神经通路的基础
调节营养不良对生殖神经内分泌功能的影响。目前还不知道如何
营养不足会破坏控制LH脉冲或激增分泌的周期或神经过程。我们提出
为了填补这一空白,通过测试整体假设:慢性营养不良扰乱卵巢周期和生育能力
通过激活NE-UCN 2-Kiss 1神经通路,损害LH分泌的两种模式:LH脉冲
和排卵前LH激增Aim 1将利用基因敲除方法研究CRHR 2的作用
在Kiss 1细胞内,作为周期中断、LH脉冲和慢性营养不良期间LH激增的介质。
目的2.1将利用一种化学方法来测试这个脑干群体是否足以损害卵巢功能。
周期,抑制AVPVKiss 1对LH峰的控制,并破坏ARCKiss 1对LH脉冲的控制。第2.2章决定
A2 NE信号传导对于卵巢周期性紊乱和搏动性排卵相关神经通路受损的必要性
LH分泌激增该项目将采用强大的生理,解剖,分子和转基因
工具,以提高我们的知识,综合应激反应和调节促性腺激素分泌。
这项提议的结果将提供对生殖代谢控制的进一步理解,
影响能量负平衡引起的无排卵障碍的管理和治疗。所有
已经有必要的动物模型和方法来完成这些研究。
英文摘要
PROJECT SUMMARY/ABSTRACT
The overall goal of this research is to understand how stress disrupts the ovarian cycle. Chronic undernutrition
is a type of metabolic stress that impairs reproduction across species, and in women is implicated in the
development of functional hypothalamic amenorrhea, an anovulatory disorder resulting from inadequate
gonadotropin secretion. Although the tight coupling of energy balance to reproductive capacity is recognized in
principle, the neuroendocrine loci and molecular mechanisms that mediate ovarian cycle dysfunction
during undernutrition remain poorly understood. In females, ovulatory cyclicity is dependent on two
populations of kisspeptin (Kiss1) neurons within the hypothalamus that coordinate gonadotropin-releasing
hormone (GnRH) and luteinizing hormone (LH) pulses and generation of the preovulatory GnRH/LH surge.
Disruption of either arcuate Kiss1 (ARCKiss1) control of LH pulses or anteroventral periventricular Kiss1
(AVPVKiss1) control of the LH surge would be anticipated to impair ovarian cyclicity in females. Our preliminary
studies demonstrate that chronic undernutrition rapidly disrupts ovarian cyclicity in female mice via
impairment of both pulsatile LH secretion and the LH surge. We show that these inhibitory effects on the
ovarian cycle are recapitulated by activation of brainstem A2NE neurons or via central administration of urocortin
2 (UCN2), a neuropeptide that specifically activates corticotropin-releasing hormone receptor 2 (CRHR2). Our
observations that antagonism of CRHR2 or knockdown of CRHR2 in Kiss1 cells diminishes reproductive
suppression in response to undernutrition or A2NE activation provide the foundation to test this neural pathway
mediating the effects of undernutrition on reproductive neuroendocrine function. Currently it is not known how
undernutrition disrupts the cycle or the neural processes controlling pulsatile or surge LH secretion. We propose
to fill this gap by testing the overall hypothesis: Chronic undernutrition disrupts the ovarian cycle and fertility
via activation of a NE – UCN2 – Kiss1 neural pathway that impairs two modes of LH secretion: LH pulses
and the preovulatory LH surge. Aim1 will utilize a genetic knockout approach to investigate the role of CRHR2
within Kiss1 cells as a mediator of disrupted cycles, LH pulses, and the LH surge during chronic undernutrition.
Aim 2.1 will utilize a chemogenic approach to test the sufficiency of this brainstem population to impair the ovarian
cycle, inhibit AVPVKiss1 control of the LH surge, and disrupt ARCKiss1 control of LH pulses. Aim 2.2 will determine
the necessity of A2NE signaling for disrupted ovarian cyclicity and impaired neural pathways underlying pulsatile
and surge LH secretion. This project will employ powerful physiological, anatomical, molecular and transgenic
tools to advance our knowledge of integrated stress responses and the regulation of gonadotropin secretion.
Results from this proposal will provide enhanced understanding of the metabolic control of reproduction that may
influence the management and treatment for anovulatory disorders resulting from negative energy balance. All
necessary animal models and methods are in place to complete these studies.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
FASEB SRC: The Mechanisms of Allostasis Conference: Stressed or Stressed Out
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批准号:10537130
-
项目类别:
-
资助金额:$2.0万
-
财政年份:2022
-
负责人:KELLIE Breen Church
-
依托单位:
Transcriptomic and epigenomic basis for reproductive dysfunction during stress
-
批准号:10394958
-
项目类别:
-
资助金额:$19.75万
-
财政年份:2021
-
负责人:KELLIE Breen Church
-
依托单位:
Regulation of gonadotropin secretion during undernutrition by a brainstem-hypothalamic neural pathway
-
批准号:10298510
-
项目类别:
-
资助金额:$52.77万
-
财政年份:2021
-
负责人:KELLIE Breen Church
-
依托单位:
Regulation of gonadotropin secretion during undernutrition by a brainstem-hypothalamic neural pathway
-
批准号:10684307
-
项目类别:
-
资助金额:$52.77万
-
财政年份:2021
-
负责人:KELLIE Breen Church
-
依托单位:
Transcriptomic and epigenomic basis for reproductive dysfunction during stress
-
批准号:10195913
-
项目类别:
-
资助金额:$23.69万
-
财政年份:2021
-
负责人:KELLIE Breen Church
-
依托单位:
Neuroendocrine Regulation of Reproduction by Glucocorticoids
-
批准号:9325553
-
项目类别:
-
资助金额:$32.16万
-
财政年份:2016
-
负责人:KELLIE Breen Church
-
依托单位:
Neuroendocrine Regulation of Reproduction by Glucocorticoids
-
批准号:9895818
-
项目类别:
-
资助金额:$32.16万
-
财政年份:2016
-
负责人:KELLIE Breen Church
-
依托单位:
Neuroendocrine Regulation of Reproduction by Glucocorticoids
-
批准号:9177432
-
项目类别:
-
资助金额:$32.16万
-
财政年份:2016
-
负责人:KELLIE Breen Church
-
依托单位:
The Role of Gonadotrope in Stress-Induced Reproductive Impairment
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批准号:7893551
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项目类别:
-
资助金额:$9.12万
-
财政年份:2010
-
负责人:KELLIE Breen Church
-
依托单位:
The Role of Gonadotrope in Stress-Induced Reproductive Impairment
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批准号:8810674
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项目类别:
-
资助金额:$22.93万
-
财政年份:2010
-
负责人:KELLIE Breen Church
-
依托单位:
The Role of Gonadotrope in Stress-Induced Reproductive Impairment
-
批准号:8066307
-
项目类别:
-
资助金额:$9.31万
-
财政年份:2010
-
负责人:KELLIE Breen Church
-
依托单位:
The Role of Gonadotrope in Stress-Induced Reproductive Impairment
-
批准号:8547860
-
项目类别:
-
资助金额:$24.9万
-
财政年份:2010
-
负责人:KELLIE Breen Church
-
依托单位:
Reproductive Suppression by Cortisol at Pituitary Gland
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批准号:6995770
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项目类别:
-
资助金额:$4.45万
-
财政年份:2005
-
负责人:KELLIE Breen Church
-
依托单位:
Reproductive Suppression by Cortisol at Pituitary Gland
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批准号:7329187
-
项目类别:
-
资助金额:$4.04万
-
财政年份:2005
-
负责人:KELLIE Breen Church
-
依托单位:
Reproductive Suppression by Cortisol at Pituitary Gland
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批准号:7327644
-
项目类别:
-
资助金额:$4.96万
-
财政年份:2005
-
负责人:KELLIE Breen Church
-
依托单位:
海外基金