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
项目摘要/摘要
这项研究的总体目标是了解压力如何扰乱卵巢周期。慢性营养不良
是一种新陈代谢应激,会损害跨物种的生殖,而在女性中,
功能性下丘脑闭经的发展,这是一种由不足引起的无排卵障碍
促性腺激素分泌。尽管能量平衡与生殖能力的紧密耦合在
调节卵巢周期功能障碍的神经内分泌基因座和分子机制
在营养不良期间,人们仍然知之甚少。在女性中,排卵的周期性取决于两个
下丘脑内协调促性腺激素释放的Kispeptin(Kiss1)神经元群
促性腺激素释放激素(GnRH)和促黄体生成素(LH)脉冲与排卵前GnRH/LH峰的产生
弓状Kiss1(ARCKiss1)对黄体生成素脉冲的控制或前腹侧脑室周围Kiss1的中断
(AVPVKiss1)控制黄体生成素激增预计会损害女性的卵巢周期。我们的预赛
研究表明,慢性营养不良通过以下途径迅速扰乱雌性小鼠的卵巢周期
促黄体生成素的搏动性分泌和促黄体生成素峰值均受损。我们表明,这些抑制作用对
激活脑干A2NE神经元或中枢注射尿皮质素可重现卵巢周期
2(UCN2),一种特异性激活促肾上腺皮质激素释放激素受体2(CRHR2)的神经肽。我们的
观察到在Kiss1细胞中CRHR2的拮抗或CRHR2的敲除会降低生殖力
对营养不良或A2NE激活的反应抑制为测试这一神经通路提供了基础
介导营养不良对生殖神经内分泌功能的影响。目前还不知道它是如何
营养不良会扰乱周期或控制促黄体生成素分泌脉动或激增的神经过程。我们建议
通过检验总体假设来填补这一空白:慢性营养不良扰乱卵巢周期和生育能力
通过激活NE-UCN2-Kiss1神经通路,损害两种方式的黄体生成素分泌:黄体生成素脉冲
排卵前促黄体生成素高峰。Aim1将利用基因敲除方法来研究CRHR2的作用
在Kiss1细胞内,作为中断周期、黄体生成素脉冲和慢性营养不良期间黄体生成素激增的中介。
Aim 2.1将利用一种化学生成方法来测试这种脑干种群是否足以损害卵巢
周期,抑制AVPVKiss1控制的黄体生成素浪涌,并中断ARCKiss1控制的黄体生成素脉冲。AIM 2.2将确定
A2NE信号在卵巢周期性紊乱和搏动性基础神经通路受损中的必要性
促黄体生成素分泌激增。该项目将采用强大的生理、解剖学、分子和转基因技术。
促进我们对综合应激反应和促性腺激素分泌调节的知识的工具。
这项建议的结果将提供对生殖代谢控制的更好理解,这可能
影响负能量平衡引起的无排卵障碍的管理和治疗。全
完成这些研究所需的动物模型和方法已经到位。
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