Contribution of estrogen receptor beta to changes in hypothalamic plasticity and hypertension susceptibility in mice with accelerated ovarian failure
雌激素受体β对卵巢加速衰竭小鼠下丘脑可塑性和高血压易感性变化的贡献
基本信息
- 批准号:9420655
- 负责人:
- 金额:$ 42.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-02-01 至 2021-01-31
- 项目状态:已结题
- 来源:
- 关键词:AgeAge-YearsAgonistAngiotensin IIAngiotensinsAntihypertensive AgentsAreaArgipressinBindingBiochemicalBiologicalBiological AssayBloodBlood PressureBrainCardiovascular systemCell membraneCorticotropin-Releasing HormoneDendritesDevelopmentDiagnosticDiseaseElectronsElectrophysiology (science)EstradiolEstrogen Receptor alphaEstrogen Receptor betaEstrogensEstrous CycleEvaluationFemaleFosteringGenesGlutamatesHormonesHumanHypertensionHypothalamic structureImmunoelectron MicroscopyIn SituIncidenceInterventionInvestigationLabelLoxP-flanked alleleMediatingMenopauseMethodsMicroscopicModelingMolecularMusN-MethylaspartateNeuronal PlasticityNeuronsNeurosecretory SystemsNitric OxideObesityOvarian hormonePathway interactionsPerimenopausePeriodicityPhasePhase TransitionPhylogenetic AnalysisPopulationPostmenopausePredispositionPremenopauseProcessProductionQuantitative Reverse Transcriptase PCRReactive Oxygen SpeciesRegulationReporterRodentRoleSignal TransductionSignaling MoleculeSliceStressSystemTestingTherapeuticTherapeutic InterventionTimeWestern BlottingWomanagedaspartate receptorblood pressure regulationcritical perioddensityhuman modelhypertension controlimmunocytochemistryinterdisciplinary approachmalemenmouse modelneurodevelopmentneurophysiologynovelolder womenovarian failureparaventricular nucleusreceptor-mediated signalingrelating to nervous systemsalt intakespatiotemporaltraffickingyoung woman
项目摘要
ABSTRACT
Hypertension is more prevalent in men than in young women, but as women progress towards
menopause this relationship is reversed. Unfortunately, compared to men, menopausal women are less
likely to receive optimal diagnostic evaluation and therapeutic intervention. In women, the increased
incidence of hypertension begins at “perimenopause”, a transitional phase preceding and extending
through menopause beginning at ~45-54 years of age. The perimenopausal period is accompanied by
irregular estrous cycles and erratically fluctuating estrogen levels; it may also be a critical period for the
emergence of brain plasticity that may contribute to the development of hypertension. The reversal of
hypertension liability in young and older women may be phylogenetically conserved: aged female mice,
but not young female mice, show increased sympathetic tone and blood pressure following slow-pressor
angiotensin II (AngII) administration. To better understand the role of ovarian hormones in female
hypertension, we have utilized a mouse model of accelerated ovarian failure (AOF) that uniquely
recapitulates hormone fluctuations seen in human menopause. Using AOF mice, we made the novel
finding that the susceptibility to hypertension begins at “peri-AOF”, which is a stage marked by irregular
and extended estrous cycles similar to human perimenopause. In addition, peri-AOF hypertension was
associated with a unique profile of N-methyl-D-aspartic acid (NMDA) receptor plasticity in estrogen
receptor β (ERβ) containing neurons in the hypothalamic paraventricular nucleus (PVN) not seen in pre- or
post-AOF females, or in males. These findings define peri-AOF as a critical period when hypertension and
adaptations in neuro-cardiovascular regulatory systems emerge. In the current proposal, we will
investigate the role of ERβ in the emergence of hypertension and PVN NMDA receptor plasticity during
peri-AOF. For this, we will test the central hypothesis that ERβ influences the susceptibility to
hypertension and NMDA receptor plasticity in select populations of PVN neurons in peri-AOF mice
following slow-pressor AngII administration. Two aims will test this hypothesis. Aim 1 will test the sub-
hypothesis that ERβ in the PVN is critically involved in the susceptibility of peri-AOF females to
hypertension and potentiated NMDA receptor-mediated excitatory signaling in CRF-expressing neurons.
Aim 2 will test the sub-hypothesis that cyclic administration of ERβ agonists during peri-AOF reduces both
hypertension susceptibility and NMDA-mediated excitatory signaling selectively in CRF-containing PVN
neurons. These studies will be achieved using a multidisciplinary approach including spatio-temporal
deletion of the ERβ gene, electron microscopic immunocytochemistry, molecular and biochemical assays
and neurophysiological methods.
抽象的
高血压在男性中比在年轻女性中更普遍,但随着女性的进步
不幸的是,与男性相比,更年期的女性较少。
在女性中,可能会得到最佳的诊断评估和治疗干预。
高血压的发病率始于“围绝经期”,这是一个提前并持续的过渡阶段
从大约 45-54 岁开始的更年期伴随着围绝经期。
不规则的发情周期和不稳定的雌激素水平波动;这也可能是一个关键时期;
大脑可塑性的出现可能有助于高血压的发展。
年轻和老年女性的高血压倾向可能在系统发育上是保守的:老年雌性小鼠,
但年轻雌性小鼠在缓慢升压后表现出交感神经张力和血压增加
血管紧张素 II (AngII) 给药 为了更好地了解卵巢激素在女性中的作用。
高血压,我们利用了卵巢加速衰竭(AOF)的小鼠模型,该模型独特地
我们利用 AOF 小鼠重现了人类更年期的激素波动。
研究发现,对高血压的易感性始于“peri-AOF”,这是一个以不规则血压为标志的阶段。
和与人类围绝经期相似的延长动情周期此外,围 AOF 高血压也是如此。
与雌激素中 N-甲基-D-天冬氨酸 (NMDA) 受体可塑性的独特特征相关
受体 β (ERβ) 包含下丘脑室旁核 (PVN) 中的神经元,在之前或之后未见
这些发现将 AOF 后期定义为高血压和高血压的关键时期。
在当前的提案中,我们将出现神经心血管调节系统的适应。
研究 ERβ 在高血压出现和 PVN NMDA 受体可塑性中的作用
为此,我们将检验 ERβ 影响敏感性的中心假设。
peri-AOF 小鼠中特定 PVN 神经元群体的高血压和 NMDA 受体可塑性
慢升压 AngII 给药后的两个目标将检验这一假设。
假设PVN中的ERβ与围AOF雌性的易感性密切相关
高血压和 CRF 表达神经元中 NMDA 受体介导的兴奋信号增强。
目标 2 将检验子假设,即在 AOF 期间循环施用 ERβ 激动剂可减少
含有 CRF 的 PVN 中高血压易感性和 NMDA 介导的兴奋信号选择性
这些研究将使用包括时空在内的多学科方法来完成。
ERβ 基因缺失、电子显微镜免疫细胞化学、分子和生化测定
和神经生理学方法。
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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MICHAEL J GLASS其他文献
MICHAEL J GLASS的其他文献
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{{ truncateString('MICHAEL J GLASS', 18)}}的其他基金
Hypothalamic cytokines, glutamate receptor plasticity, and blood pressure
下丘脑细胞因子、谷氨酸受体可塑性和血压
- 批准号:
9383481 - 财政年份:2017
- 资助金额:
$ 42.38万 - 项目类别:
Contribution of G protein coupled estrogen receptor to changes in hypothalamic plasticity and hypertension susceptibility in mice with accelerated ovarian failure
G蛋白偶联雌激素受体对卵巢加速衰竭小鼠下丘脑可塑性和高血压易感性变化的影响
- 批准号:
10586855 - 财政年份:2017
- 资助金额:
$ 42.38万 - 项目类别:
GLUTAMATE RECEPTORS AND OPIOID DEPENDENCE: MOLECULES, CIRCUITS AND BEHAVIOR
谷氨酸受体和阿片类药物依赖性:分子、电路和行为
- 批准号:
7766956 - 财政年份:2009
- 资助金额:
$ 42.38万 - 项目类别:
GLUTAMATE RECEPTORS AND OPIOID DEPENDENCE: MOLECULES, CIRCUITS AND BEHAVIOR
谷氨酸受体和阿片类药物依赖性:分子、电路和行为
- 批准号:
8017415 - 财政年份:2009
- 资助金额:
$ 42.38万 - 项目类别:
AMYGDALA AMPA GLUR2 DELETION AND OPIOID DEPENDENCE
杏仁核 AMPA GLUR2 缺失和阿片类药物依赖性
- 批准号:
7894962 - 财政年份:2009
- 资助金额:
$ 42.38万 - 项目类别:
GLUTAMATE RECEPTORS AND OPIOID DEPENDENCE: MOLECULES, CIRCUITS AND BEHAVIOR
谷氨酸受体和阿片类药物依赖性:分子、电路和行为
- 批准号:
8215752 - 财政年份:2009
- 资助金额:
$ 42.38万 - 项目类别:
GLUTAMATE RECEPTORS AND OPIOID DEPENDENCE: MOLECULES, CIRCUITS AND BEHAVIOR
谷氨酸受体和阿片类药物依赖性:分子、电路和行为
- 批准号:
8415890 - 财政年份:2009
- 资助金额:
$ 42.38万 - 项目类别:
GLUTAMATE RECEPTORS AND OPIOID DEPENDENCE: MOLECULES, CIRCUITS AND BEHAVIOR
谷氨酸受体和阿片类药物依赖性:分子、电路和行为
- 批准号:
7532564 - 财政年份:2009
- 资助金额:
$ 42.38万 - 项目类别:
AMYGDALA AMPA GLUR2 DELETION AND OPIOID DEPENDENCE
杏仁核 AMPA GLUR2 缺失和阿片类药物依赖性
- 批准号:
7712282 - 财政年份:2009
- 资助金额:
$ 42.38万 - 项目类别:
Opioids and Conditional Amygdala NMDA Receptor Knockout
阿片类药物和条件性杏仁核 NMDA 受体敲除
- 批准号:
7033079 - 财政年份:2004
- 资助金额:
$ 42.38万 - 项目类别:
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