DENDRITIC RELEASE OF NEUROPEPTIDES: ROLE IN BODILY HOMEOSTASIS
神经肽的树突释放:在身体稳态中的作用
基本信息
- 批准号:9769162
- 负责人:
- 金额:$ 25.54万
- 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:2018-01-01 至 2021-07-31
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAstrocytesAxonBindingChronicCommunicationDataDendritesDevelopmentDiabetes MellitusDiffuseDiffusionDiseaseElectrolytesExcess Dietary SaltExtracellular SpaceFeedbackGenerationsGlutamatesHealthHeart failureHomeostasisHypertensionHypothalamic structureLiquid substanceMediatingMetabolic syndromeModelingMonitorMorbidity - disease rateN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNeuraxisNeuronsNeuropeptidesNeurosecretory SystemsPatientsPatternPhysiologicalPituitary GlandPlayPopulationPotassium ChannelPresynaptic TerminalsProcessReceptor ActivationRegulationRoleSeriesSignal TransductionSodium ChlorideStressSystemTestingTherapeuticTimeVasopressinsWireless TechnologyWorkclinically significantinnovationinterdisciplinary approachmagnocellularmortalitymultimodalityneuronal cell bodynovelosmoreceptoroutcome forecastparaventricular nucleusreceptorresponsesalt intaketreatment strategy
项目摘要
Bodily homeostasis involves orchestrated activities between hypothalamic autonomic and neuroendocrine
neuronal networks. Importantly, an imbalanced interaction between them constitutes the basis for
maladaptive responses (“neurohumoral activation”) observed in disease conditions (stress, heart failure and
the metabolic syndrome). Importantly, neurohumoral activation (which includes centrally driven sympathetic
activity and elevated circulating levels of vasopressin (VP)) directly correlates with prognosis, and mortality in
these diseases. Thus, understanding the mechanisms involved in autonomic and neuroendocrine integration,
both in health and disease conditions, is of critical physiological and clinical significance. The hypothalamic
paraventricular nucleus (PVN) plays a pivotal role in the generation of coordinated polymodal homeostatic
responses. Still, the mechanism by which the activity of these functionally distinct neuronal populations is
orchestrated during a homeostatic response remains elusive. We recently identified dendritic release of VP
from magnocellular neurosecretory neurons as a novel signaling mechanism underlying “wireless” (non-
synaptic) communication between neuroendocrine and presympathetic PVN neurons. We showed this
interpopulation crosstalk to play a major role coordinated neurosecretory/sympathetic homeostatic responses
to an osmotic challenge (OSM+). While significant progress has been obtained in our understanding of
mechanisms underlying activity-dependent release of neuropeptides from axonal terminals, limited information
is available regarding mechanisms regulating dendritic release, particularly during OSM+. Thus, we implemented a
highly innovative approach that enables us to quantitatively monitor dendritic VP release in real time, while
studying in a mechanistic manner the main processes involved in this interpopulation homeostatic crosstalk.
We obtained exciting preliminary data that supports our innovative hypothesis of a fine-tuned interplay
between glutamate NMDA receptors (NMDARs), backpropagating dendritic action potentials and K+ channels
in regulating dendritic VP release and neurosecretory-presympathetic signaling crosstalk in response to OSM+.
Moreover, we will test the hypothesis that astrocytes, recognized as key players in CNS function, exert a
pivotal influencing dendritic release of VP, its diffusing efficacy in the ECS, and ultimately, the generation of
multimodal homeostatic responses. These hypotheses will be tested in 3 specific aims: 1- To elucidate
mechanisms by which action potentials (APs) and NMDARs interact during OSM+ to evoke dendritic VP
release. 2- To elucidate mechanisms that regulate dendritic retrograde signaling and their impact on
dendritic release. 3- To elucidate mechanisms that control the diffusion of VP in the extracellular space,
influencing in turn its efficacy as an interpopulation signaling. We expect results from this work to broaden
our understanding of basic cellular mechanisms contributing to the hypothalamic regulation of homeostasis,
and how changes in these mechanisms may contribute to neurohumoral activation during disease states.
身体稳态涉及下丘脑自主神经和神经内分泌之间的协调活动
神经元网络。重要的是,它们之间的不平衡相互作用构成了
在疾病状况(压力、心力衰竭和
代谢综合征)。重要的是,神经体液激活(包括中枢驱动的交感神经
加压素(VP)的活性和循环水平升高与预后和死亡率直接相关
这些疾病。因此,了解自主神经和神经内分泌整合所涉及的机制,
无论在健康还是疾病条件下,都具有至关重要的生理和临床意义。下丘脑
室旁核(PVN)在协调多模式稳态的产生中起着关键作用
回应。尽管如此,这些功能不同的神经元群体的活动机制仍然是不同的。
在稳态反应期间精心策划的仍然难以捉摸。我们最近发现了 VP 的树突释放
来自大细胞神经分泌神经元作为“无线”(非-
突触)神经内分泌和交感前 PVN 神经元之间的通讯。我们展示了这个
群体间串扰在协调神经分泌/交感稳态反应中发挥重要作用
渗透压挑战 (OSM+)。虽然我们在认识上取得了重大进展
轴突末梢神经肽活性依赖性释放的机制,信息有限
有关调节树突释放的机制,特别是在 OSM+ 期间。因此,我们实施了一个
高度创新的方法使我们能够实时定量监测树突 VP 的释放,同时
以机械方式研究这种群体间稳态串扰所涉及的主要过程。
我们获得了令人兴奋的初步数据,支持我们关于微调相互作用的创新假设
谷氨酸 NMDA 受体 (NMDAR)、反向传播树突动作电位和 K+ 通道之间
调节树突状 VP 释放和响应 OSM+ 的神经分泌-前交感神经信号串扰。
此外,我们将检验以下假设:星形胶质细胞被认为是中枢神经系统功能的关键参与者,发挥着
VP 的树突释放、其在 ECS 中的扩散功效以及最终的生成具有关键影响
多模式稳态反应。这些假设将在 3 个具体目标中进行测试: 1- 阐明
OSM+ 期间动作电位 (AP) 和 NMDAR 相互作用以诱发树突 VP 的机制
发布。 2-阐明调节树突逆行信号传导的机制及其对
树突释放。 3- 阐明控制 VP 在细胞外空间扩散的机制,
进而影响其作为群体间信号传导的功效。我们期望这项工作的成果能够扩大
我们对有助于下丘脑稳态调节的基本细胞机制的理解,
以及这些机制的变化如何有助于疾病状态下的神经体液激活。
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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Javier E Stern其他文献
Javier E Stern的其他文献
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{{ truncateString('Javier E Stern', 18)}}的其他基金
Novel SCN-OVLT portal system: Dissecting Anatomical and Functional Properties
新型 SCN-OVLT 门户系统:剖析解剖和功能特性
- 批准号:
10754088 - 财政年份:2023
- 资助金额:
$ 25.54万 - 项目类别:
DENDRITIC RELEASE OF NEUROPEPTIDES: ROLE IN BODILY HOMEOSTASIS
神经肽的树突释放:在身体稳态中的作用
- 批准号:
9618919 - 财政年份:2018
- 资助金额:
$ 25.54万 - 项目类别:
Central neuronal-glial mechanisms and neurohumoral activation in hypertension
高血压的中枢神经元神经胶质机制和神经体液激活
- 批准号:
8373050 - 财政年份:2012
- 资助金额:
$ 25.54万 - 项目类别:
Central neuronal-glial mechanisms and neurohumoral activation in hypertension
高血压的中枢神经元神经胶质机制和神经体液激活
- 批准号:
8669816 - 财政年份:2012
- 资助金额:
$ 25.54万 - 项目类别:
CO regulation of hypothalamic neuronal activity in health and disease states
健康和疾病状态下丘脑神经元活动的 CO 调节
- 批准号:
8458529 - 财政年份:2012
- 资助金额:
$ 25.54万 - 项目类别:
CO regulation of hypothalamic neuronal activity in health and disease states
健康和疾病状态下丘脑神经元活动的 CO 调节
- 批准号:
8282375 - 财政年份:2012
- 资助金额:
$ 25.54万 - 项目类别:
Central neuronal-glial mechanisms and neurohumoral activation in hypertension
高血压的中枢神经元神经胶质机制和神经体液激活
- 批准号:
8477277 - 财政年份:2012
- 资助金额:
$ 25.54万 - 项目类别:
CENTRAL NEURONAL-GLIAL MECHANISMS AND NEUROHUMORAL ACTIVATION IN HYPERTENSION
高血压的中枢神经元神经胶质机制和神经体液激活
- 批准号:
9618915 - 财政年份:2012
- 资助金额:
$ 25.54万 - 项目类别:
Altered CNS intercellular signaling mechanisms in cardiovascular disease
心血管疾病中中枢神经系统细胞间信号传导机制的改变
- 批准号:
8011516 - 财政年份:2008
- 资助金额:
$ 25.54万 - 项目类别:
Altered CNS Intercellular Signaling Mechanisms in Cardiovascular Disease
心血管疾病中中枢神经系统细胞间信号传导机制的改变
- 批准号:
9084606 - 财政年份:2008
- 资助金额:
$ 25.54万 - 项目类别:
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