Arcuate ERa Signaling in Central Control of Female Bone Metabolism
女性骨代谢中枢控制的弓形 ERa 信号传导
基本信息
- 批准号:10417070
- 负责人:
- 金额:$ 46.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-30 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAge-Related Bone LossBiological AssayBone DensityBrainCell NucleusDataDoseEndocrineEnergy MetabolismEstradiolEstrogen Receptor alphaEstrogensExhibitsExposure toFemaleGatekeepingGeneticGenetic ModelsGoalsGonadal Steroid HormonesHealthHormonalHumanHypothalamic structureIn VitroKISS1 geneKnowledgeLeptinLongevityMedialMediatingMetabolicMetabolismModelingMolecularMusNervous System controlNeuraxisNeuronsOsteogenesisOsteoporosisParabiosisPeripheralPharmaceutical PreparationsPharmacologyPhenotypePhysiologyPublic HealthRegulationReportingReproductionResearchRosaniline DyesSex DifferencesSignal TransductionSteroidal EstrogenStructure of nucleus infundibularis hypothalamiTestingTestosteroneTherapeuticTissuesTranslationsVirusWorkbonebone fracture repairbone massbone metabolismbone strengthcortical bonedesigner receptors exclusively activated by designer drugsenergy balancehormonal signalsin vivomalemouse modelmutantmutant mouse modelneural circuitnovelnovel therapeuticspre-clinicalrational designreproductive fitnessresponsesexskeletalsubstantia spongiosatranslational potential
项目摘要
Project Summary/Abstract
In this revised R01 application we will ask how estrogen signaling in the central nervous system controls
bone metabolism in a sex dependent manner. It is well known that peripheral estrogen affects bone in
both mice and humans. As part of our efforts to understand how estrogen neural circuits in mice affect
female metabolism, we discovered that estrogen signaling in the arcuate nucleus (ARC) of the
hypothalamus normally suppresses cortical and trabecular bone mass in female mice. Ablating estrogen
receptor alpha (ERa) in three intersectional and independent mouse models leads to a striking high bone
mass phenotype in female mice; male bones are unaffected. Mutant females exhibit exceptionally dense
trabecular and cortical bones, whose strengths surpass other reported mouse models. Stereotaxic-
guided deletion of brain ERa confirmed the central origin of this bone phenotype and uncoupled this
phenotype from changes in circulating estradiol, testosterone, or leptin. Our work defines central
regulation of bone metabolism, alongside reproduction and energy balance, as a fundamental sex-
difference in physiology. These data also offer proof for the concept that the brain is a major determinant
of female bone metabolism, thus expanding the gatekeeper function of the hypothalamus in energy
expenditure to non-classical metabolic tissues, such as bone. Although our research is in the earliest
pre-clinical stages, understanding how our models build massively dense and strong bones could
transform current rational design of therapeutics for hormonal and age-related bone loss. Why and how
female ARC neurons normally inhibit bone metabolism remain a mystery. In the following three aims, we
seek to unravel this puzzle. We will define and then confirm which ARC neurons mediate this brain-bone
connection, ask if manipulating these neurons via chemogenetics and pharmacology mimics high bone
phenotype or normalizes the bone phenotype in mutants, and then begin determining the molecular
basis for this sex-dependent high bone phenotype.
项目总结/摘要
在这个修改后的R 01应用程序中,我们将询问中枢神经系统中的雌激素信号如何控制
以性别依赖的方式进行骨代谢。众所周知,外周雌激素影响骨,
老鼠和人类都是。作为我们努力了解小鼠雌激素神经回路如何影响
女性代谢,我们发现,在弓状核(ARC)的雌激素信号,
下丘脑通常抑制雌性小鼠的皮质骨和小梁骨质量。促雌激素
受体α(ER α)在三个交叉和独立的小鼠模型中导致了惊人的高骨密度,
雌性小鼠中的mass表型;雄性骨骼不受影响。变异雌性会表现出
骨小梁和皮质骨,其强度超过其他报道的小鼠模型。立体定位-
脑ER α的引导性缺失证实了这种骨表型的中心起源,
表型从循环雌二醇,睾酮或瘦素的变化。我们的工作定义了中心
调节骨代谢,以及生殖和能量平衡,作为一个基本的性别-
生理上的差异。这些数据也为大脑是一个主要决定因素的概念提供了证据
女性骨代谢,从而扩大了下丘脑在能量方面的看门人功能
消耗到非经典的代谢组织,如骨。虽然我们的研究是在最早的
临床前阶段,了解我们的模型如何建立大规模密集和强大的骨骼,
改变目前激素和年龄相关骨质流失治疗的合理设计。为什么和如何
女性ARC神经元通常抑制骨代谢仍然是一个谜。在以下三个目标中,我们
试图解开这个谜团我们将定义并确认哪些ARC神经元介导这种脑-骨
连接,询问是否通过化学遗传学和药理学操纵这些神经元模仿高骨
表型或使突变体中的骨表型正常化,然后开始确定突变体的分子表型。
这种性别依赖性高骨表型的基础。
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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HOLLY A. INGRAHAM其他文献
HOLLY A. INGRAHAM的其他文献
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{{ truncateString('HOLLY A. INGRAHAM', 18)}}的其他基金
Dissecting a hormone-responsive processor for female activity and repetitive behavior
剖析女性活动和重复行为的激素反应处理器
- 批准号:
10796627 - 财政年份:2023
- 资助金额:
$ 46.84万 - 项目类别:
Understanding Mechanisms and Sex-Differences in Visceral Pain
了解内脏疼痛的机制和性别差异
- 批准号:
10635564 - 财政年份:2023
- 资助金额:
$ 46.84万 - 项目类别:
Dissecting a hormone-responsive processor for female activity and repetitive behavior
剖析女性活动和重复行为的激素反应处理器
- 批准号:
10578739 - 财政年份:2020
- 资助金额:
$ 46.84万 - 项目类别:
Dissecting a hormone-responsive processor for female activity and repetitive behavior
剖析女性活动和重复行为的激素反应处理器
- 批准号:
10562964 - 财政年份:2020
- 资助金额:
$ 46.84万 - 项目类别:
Dissecting a hormone-responsive processor for female activity and repetitive behavior
剖析女性活动和重复行为的激素反应处理器
- 批准号:
10115716 - 财政年份:2020
- 资助金额:
$ 46.84万 - 项目类别:
Dissecting a hormone-responsive processor for female activity and repetitive behavior
剖析女性活动和重复行为的激素反应处理器
- 批准号:
10361212 - 财政年份:2020
- 资助金额:
$ 46.84万 - 项目类别:
Arcuate ERa Signaling in Central Control of Female Bone Metabolism
女性骨代谢中枢控制的弓形 ERa 信号传导
- 批准号:
9916919 - 财政年份:2019
- 资助金额:
$ 46.84万 - 项目类别:
Mapping gut-spinal cord connections in visceral pain
绘制内脏疼痛中的肠-脊髓连接图
- 批准号:
10023951 - 财政年份:2019
- 资助金额:
$ 46.84万 - 项目类别:
Mapping gut-spinal cord connections in visceral pain
绘制内脏疼痛中的肠-脊髓连接图
- 批准号:
10242195 - 财政年份:2019
- 资助金额:
$ 46.84万 - 项目类别:
Arcuate ERa Signaling in Central Control of Female Bone Metabolism
女性骨代谢中枢控制的弓形 ERa 信号传导
- 批准号:
10634591 - 财政年份:2019
- 资助金额:
$ 46.84万 - 项目类别:
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