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
基本信息
- 批准号:8458529
- 负责人:
- 金额:$ 17.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-04-16 至 2015-01-31
- 项目状态:已结题
- 来源:
- 关键词:Angiotensin IIAnimal ModelAreaAstrocytesBiological AvailabilityBrainBrain regionCarbon MonoxideCell NucleusCellsCongestive Heart FailureDataDevelopmentDiseaseDisinhibitionElectrophysiology (science)EnzymesEquilibriumFluorescent DyesGasesGenerationsGoalsHealthHeart failureHemeHomeostasisHypothalamic structureImmunohistochemistryIn VitroKnowledgeLeadMaintenanceMeasuresMediatingMicrogliaModelingMonitorMorbidity - disease rateNeuraxisNeuronsNeurosecretory SystemsNeurotransmittersNitric OxideOutputOxygenasesPathologic ProcessesPatientsPeripheralPhysiologicalPlasmaPlayPopulationPreventionProductionPublic HealthRattusRegulationReportingRoleSeriesSignal TransductionSignaling MoleculeSourceSystemTestingTherapeuticVasopressinsWorkcellular imagingcellular targetingcomplement C2adisease characteristicgamma-Aminobutyric Acidhuman diseaseinterdisciplinary approachmortalitynovelparaventricular nucleuspatch clampresponsetreatment strategy
项目摘要
DESCRIPTION (provided by applicant): While coordinated activities of the sympathetic and neuroendocrine systems are essential for proper maintenance of bodily homeostasis, sustained sympathohumoral activation is highly detrimental, contributing to several prevalent diseases, including heart failure (HF). Despite this evidence, a comprehensive understanding of the basic mechanisms underlying neurohumoral responses both in physiological and pathological conditions is still missing. The hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei play pivotal roles in the generation of sympathohumoral responses, and accumulating evidence supports elevated neuronal activity in these nuclei in animal models of HF. However, the precise underlying mechanisms remain incompletely understood. The atypical gas neurotransmitters, particularly nitric oxide (NO), are recognized as critical inhibitory signaling molecules in the brain, mostly in areas involved in autonomic/neuroendocrine integration. In fact, a blunted NO function has been shown to contribute to sympathohumoral activation in HF. Here, we propose the gas molecule carbon monoxide (CO) as a novel signaling mechanism within the SON/PVN. We obtained preliminary results showing that in opposition to NO, CO stimulates hypothalamic neuronal function. Thus, we put forward the novel concept that a balance between two opposing gas molecules is critical in determining neurohumoral outflows from the hypothalamus. Using a multidisciplinary approach combining in vitro electrophysiology, cell imaging, tract tracing and immunohistochemistry, we will test the central hypothesis that elevated CO bioavailability contributes to exacerbated SON/PVN neuronal activity in HF, and that these effects are mediated by blunting NO inhibitory function. We will test our central hypothesis in 2 specific aims: 1 - To determine the specific cellular sources of CO within the SON/PVN in sham and HF rats. Our working hypothesis is that the CO-synthetizing enzyme heme-oxygenase (HO) is expressed in specific cell populations within the SON/PVN, and that an elevated expression occurs in HF rats. 2 - To determine the cellular targets and mechanisms of action of CO within the SON/PVN in sham and HF rats. Our working hypothesis is that CO is an excitatory gas molecule targeting both neurosecretory and presympathetic neurons. We expect results from this R21 proposal to provide the proof-of-concept that CO is endogenously produced within the SON and PVN, and that it is a functionally relevant gas molecule influencing neuronal activity in these brain regions. We will begin to understand how changes in CO/NO interactions contribute to altered neuronal activity, and consequently neurohumoral output in an animal model of HF. We believe this knowledge will broaden our understanding of basic cellular mechanisms contributing to the hypothalamic control of homeostasis, as well as how changes in these mechanisms lead to pathological process in prevalent human diseases.
描述(由申请人提供):虽然交感神经和神经内分泌系统的协调活动对于适当维持身体稳态至关重要,但持续的交感体液激活是非常有害的,会导致几种常见疾病,包括心力衰竭(HF)。尽管有这些证据,但对生理和病理条件下神经体液反应的基本机制的全面理解仍然缺失。下丘脑室旁核(PVN)和视上核(SON)在交感体液反应的产生中起着关键作用,越来越多的证据支持HF动物模型中这些核中神经元活性升高。然而,确切的基本机制仍然不完全清楚。非典型气体神经递质,特别是一氧化氮(NO),被认为是关键的抑制性信号分子在大脑中,主要是在涉及自主神经/神经内分泌整合的领域。事实上,钝化的NO功能已被证明有助于HF中的交感体液激活。在这里,我们提出的气体分子一氧化碳(CO)作为一种新的信号机制内的SON/PVN。我们获得的初步结果表明,在反对NO,CO刺激下丘脑神经元功能。因此,我们提出了一个新的概念,两个相反的气体分子之间的平衡是决定神经体液流出下丘脑的关键。使用多学科的方法结合体外电生理学,细胞成像,束跟踪和免疫组化,我们将测试中心的假设,提高CO生物利用度有助于加剧SON/PVN神经元活动在HF,这些影响是由钝化NO抑制功能介导的。我们将在2个具体目标中测试我们的中心假设:1 -确定假手术和HF大鼠中SON/PVN内CO的特定细胞来源。我们的工作假设是CO合成酶血红素加氧酶(HO)在SON/PVN内的特定细胞群中表达,并且在HF大鼠中表达升高。2.确定CO在假手术和HF大鼠SON/PVN中的细胞靶点和作用机制。我们的工作假设是,CO是一种兴奋性气体分子,靶向神经分泌和前交感神经元。我们期望从这个R21提案的结果提供的概念证明,CO是内源性的SON和PVN内产生的,它是一个功能相关的气体分子影响神经元活动在这些大脑区域。我们将开始了解CO/NO相互作用的变化如何影响HF动物模型中神经元活动的改变,从而影响神经体液输出。我们相信这些知识将拓宽我们对下丘脑控制稳态的基本细胞机制的理解,以及这些机制的变化如何导致人类流行疾病的病理过程。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Physiological regulation of magnocellular neurosecretory cell activity: integration of intrinsic, local and afferent mechanisms.
- DOI:10.1111/jne.12051
- 发表时间:2013-08
- 期刊:
- 影响因子:3.2
- 作者:Brown CH;Bains JS;Ludwig M;Stern JE
- 通讯作者:Stern JE
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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
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- 批准号:
10754088 - 财政年份:2023
- 资助金额:
$ 17.85万 - 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
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9618919 - 财政年份:2018
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$ 17.85万 - 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:
9769162 - 财政年份:2018
- 资助金额:
$ 17.85万 - 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:
$ 17.85万 - 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:
$ 17.85万 - 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:
$ 17.85万 - 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:
$ 17.85万 - 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:
$ 17.85万 - 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:
$ 17.85万 - 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:
$ 17.85万 - 项目类别:
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