Regulation of neuro-cardiovascular function during stress
应激期间神经心血管功能的调节
基本信息
- 批准号:9239217
- 负责人:
- 金额:--
- 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:2017-01-01 至 2020-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAirAnimal ModelAssessment toolAttenuatedAutonomic nervous systemBloodBlood - brain barrier anatomyBlood PressureBlood VesselsBrainCardiacCardiovascular DiseasesCardiovascular PhysiologyCardiovascular systemCell NucleusCellsCessation of lifeChloride IonChloridesChronicChronic DiseaseChronic stressClinical TrialsConsciousCorticotropinDehydrationDendritesDepressed moodDevelopmentDiseaseExposure toFemaleFoundationsGeneral PopulationGeneticGoalsHeart RateHeart failureHormonesHydrocortisoneHyperactive behaviorIndividualKidneyLaboratoriesLinkMeasurementMediatingMental DepressionMilitary PersonnelModelingMonitorMorbidity - disease rateMyocardial InfarctionNerveNeuraxisNeuronsOutputPeripheralPharmacologyPituitary GlandPotassium ChlorideRattusReceptor ActivationReflex actionRegulationResearch PersonnelRiskRisk FactorsRodent ModelRoleSignal TransductionSmall Interfering RNASodiumSodium ChlorideSprague-Dawley RatsStimulusStressStrokeSympathetic Nervous SystemSystemTailTelemetryTestingTimeVasopressin ReceptorVasopressinsVeteransWaterWater Stressacute stressbehavioral responsebiological adaptation to stresscardiovascular risk factorcombatdepression modeldesigndisorder riskexperiencegamma-Aminobutyric Acidhemodynamicshigh riskhypothalamic-pituitary-adrenal axisimproved outcomeinstrumentknock-downmagnocellularmalemortalitynovel therapeutic interventionnovel therapeuticsparaventricular nucleusphase I trialpreclinical studypressurepreventreceptorresponserestraint stressstress disorderstressorsupraoptic nucleussymporter
项目摘要
Cardiovascular morbidity and mortality is higher among Veterans than the general population independent of
factors such as chronic illnesses or socio-econamic status. Depression is now recognized as a non-traditional
risk factor for cardiovascular disease. Nearly one-third of Veterans suffer from depression at some point,
regardless of whether they have been deployed in combat. Activation of vasopressin (AVP) receptors within
the central nervous system, specifically the paraventricular nucleus (PVN) has been implicated in depression.
Recent studies have shown that AVP is released from dendrites within the PVN and that central AVP mediates
the sympathoexcitation observed heart failure. Sympathoexcitation is also strongly associated with greater
cardiovascular risk. Notably, gamma-aminobutyric acid (GABA) typically suppresses sympathoexcitation. New
evidence indicates that GABA may exert a paradoxically stimulatory effect on AVP signaling due to plasticity
that occurs in the chloride ion concentration within neurons. The intracellular chloride concentration is
controlled by chloride transport via the sodium chloride co-transporter 1 (NKCC1) which transports chloride ion
into the cell or the potassium chloride co-transporter 2 (KCC2) which extrudes chloride ion. Thus, we
hypothesize that AVP activates V1a receptors (V1aR) and/or V1b receptors (V1bR) within the PVN to increase
arterial pressure, heart rate and sympathetic activity thereby contributing to the augmentation of these
responses to acute stress in an animal model of depression. Three specific aims will be addressed. In Specific
Aim 1, we will use pharmacologic inhibition and genetic knockdown with siRNA approaches to assess whether
exogenous AVP activation of V1aR or V1bR alone or in combination results in increased arterial pressure, heart
rate and RSNA and exaggerated responses to acute stress. In Specific Aim 2, we will test whether changes in
NKCC1 or KCC2 transport in PVN attenuate, or even reverse, GABAergic inhibition of hemodynamic and
RSNA responses to V1aR and/or V1bR activation in the basal state or during acute stress. In Specific Aim 3, we
will ascertain whether endogenous AVP within the PVN activates V1aR and/or V1bR thereby contributing to the
increased arterial pressure and RSNA in a rat model of chronic unpredictable stress (CMS), a validated model
of depression, and whether increased transport via NKCC1 or decreased transport via KCC2 prevents
GABAergic suppression of these responses. We will test this hypothesis in conscious, unrestrained Sprague
Dawley rats chronically-instrumented with telemetry transmitters for both hemodynamic and nerve activity
measurements. The ability to monitor not only arterial pressure but also RSNA by telemetry in conscious rats
has been mastered by only a few laboratories including our own and provides a powerful tool for assessment
of basal and stress conditions with minimal investigator interference. We will identify the contribution of the
vasopressinergic receptor(s) involved in the responses to exogenous AVP as well as to acute stressors: air jet,
nasopharyngeal reflex, tail in 50°C water, and restraint stress. We will then ascertain whether GABA inhibition
of AVP signaling is altered by blockade of NKCC1 or KCC2. Then, we will subject the rats to CMS and assess
whether blockade of V1aR and/or V1bR decreases baseline arterial pressure, heart rate and RSNA. We will
evaluate whether CMS predisposes to enhanced responses to acute stressors and if that response is due to
vasopressinergic signaling that may be impacted by plasticity of the GABAergic system. With the exciting
advent of new brain-permeant, highly selective V1aR antagonists already in phase I trials in other disorders, the
need for studying V1aR and V1bR antagonism in stress disorders is timely and distinctly translatable for
treatment of people with chronic stress such as depression. The proposed studies will provide the crucial
rationale and robust mechanistic evidence upon which to design a clinical trial. Given that our Veterans
experience both depression and a high risk for cardiovascular morbidity and mortality, the proposed pre-clinical
studies will lay a vital foundation for new adjunctive treatments to improve outcomes for depressed Veterans.
退伍军人的心血管发病率和死亡率高于一般人群,与此无关
慢性疾病或社会经济状况等因素。抑郁症现在被认为是非传统的
心血管疾病的危险因素。近三分之一的退伍军人在某个时候患有抑郁症,
无论他们是否在战斗中被部署。血管加压素(AVP)受体的激活
中枢神经系统,特别是室旁核(PVN)与抑郁症有关。
最近的研究表明,AVP是从PVN内的树突释放的,并且中枢AVP介导
交感神经兴奋观察到心力衰竭。交感兴奋也与更大的
心血管风险值得注意的是,γ-氨基丁酸(GABA)通常抑制交感神经兴奋。新
有证据表明,GABA可能由于可塑性而对AVP信号产生矛盾的刺激作用
这发生在神经元内的氯离子浓度。细胞内氯离子浓度是
通过转运氯离子的氯化钠协同转运蛋白1(NKCC 1)的氯转运控制
进入细胞或氯化钾协同转运蛋白2(KCC2),它排出氯离子。因此我们
假设AVP激活PVN内的V1a受体(V1aR)和/或V1b受体(V1bR),
动脉压,心率和交感神经活动,从而有助于增加这些
抑郁症动物模型对急性应激的反应。将讨论三个具体目标。在特定
目的1,我们将使用药理学抑制和基因敲低siRNA方法来评估是否
V1aR或V1bR单独或组合的外源性AVP激活导致动脉压升高,心脏
率和RSNA和夸张的反应,急性应激。在具体目标2中,我们将测试
室旁核中NKCC 1或KCC 2的转运减弱甚至逆转了GABA能对血流动力学的抑制,
RSNA对基础状态或急性应激期间V1aR和/或V1bR激活的反应。在具体目标3中,我们
将确定PVN内的内源性AVP是否激活V1aR和/或V1bR,从而有助于
慢性不可预测应激(CMS)大鼠模型中动脉压和RSNA升高,
以及通过NKCC 1增加转运或通过KCC 2减少转运是否阻止了抑郁症的发生。
GABA能抑制这些反应。我们将在有意识的、无拘无束的斯普拉格身上检验这一假设
道利大鼠长期使用遥测发射器监测血流动力学和神经活动
测量.在清醒大鼠中通过遥测不仅监测动脉压而且监测RSNA的能力
只有包括我们自己的实验室在内的少数实验室掌握了这一技术,并为评估提供了强有力的工具
在基础和应激条件下,最小限度地减少研究者的干扰。我们将确定
参与对外源性AVP以及急性应激源的反应的血管加压素能受体:空气喷射,
鼻咽反射、50 ° C水中的尾部和束缚应激。然后我们将确定GABA抑制
AVP信号传导的改变是通过阻断NKCC1或KCC2来实现的。然后,我们将对大鼠进行CMS并评估
V1aR和/或V1bR阻滞是否降低基线动脉压、心率和RSNA。我们将
评估CMS是否倾向于对急性应激源的反应增强,以及这种反应是否是由于
可能受GABA能系统可塑性影响的血管加压素能信号传导。进行令人兴奋的
新的脑渗透性,高选择性V1aR拮抗剂的出现已经在其他疾病的I期试验中,
研究应激障碍中V1aR和V1bR拮抗作用的需要是及时和明确的,
治疗慢性压力患者,如抑郁症。拟议的研究将提供关键的
设计临床试验的基本原理和可靠的机制证据。鉴于我们的退伍军人
经历抑郁症和高风险的心血管疾病的发病率和死亡率,建议临床前
研究将为新的连续治疗奠定重要的基础,以改善抑郁症退伍军人的结果。
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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Noreen F Rossi其他文献
Noreen F Rossi的其他文献
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{{ truncateString('Noreen F Rossi', 18)}}的其他基金
Impact of Dietary Fructose and High Salt Diet on Neurocardiovascular and Renal Function
膳食果糖和高盐饮食对神经心血管和肾功能的影响
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10593164 - 财政年份:2022
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Impact of Dietary Fructose and High Salt Diet on Neurocardiovascular and Renal Function
膳食果糖和高盐饮食对神经心血管和肾功能的影响
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Regulation of neuro-cardiovascular function during stress
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- 批准号:
9397964 - 财政年份:2017
- 资助金额:
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Regulation of neuro-cardiovascular function during stress
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Exercise Training and Blood Pressure in Hypertension: Integrated Mechanisms
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9315582 - 财政年份:2012
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- 批准号:
8278294 - 财政年份:2012
- 资助金额:
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- 批准号:
10174722 - 财政年份:2012
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- 批准号:
8838219 - 财政年份:2012
- 资助金额:
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Neural Control of Sodium Balance in Hypertension: Exercise
高血压钠平衡的神经控制:运动
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