Negative Impact of Alcohol on Cardiovascular Neurobiology
酒精对心血管神经生物学的负面影响
基本信息
- 批准号:8050630
- 负责人:
- 金额:$ 45.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1988
- 资助国家:美国
- 起止时间:1988-09-01 至 2013-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcetaldehydeAcuteAddressAdoptedAdverse effectsAlcohol consumptionAlcoholsAnimal ModelAreaBaroreflexBindingBiological ModelsBiologyBlood PressureBrainBrain StemCalmodulinCarbon MonoxideCardiacCardiovascular systemCatabolismCaveolinsConsciousDoseEnzymesEssential HypertensionEthanolExperimental DesignsExperimental ModelsFOS geneFunctional disorderGene ProteinsGeneticHealthHemeHumanHypertensionImmunoprecipitationInbred SHR RatsInbred WKY RatsInterventionJUN geneKnowledgeMAP Kinase GeneMAPK14 geneMAPK8 geneMediatingMetabolicModelingMolecularMolecular ProbesNeurobiologyNeuronsNorepinephrineNucleus solitariusOxygenasesPathway interactionsPhosphorylationProteinsRattusReflex actionResearchResearch PersonnelRoleSecond Messenger SystemsSeriesSignal TransductionSiteSmall Interfering RNASpatial DistributionTestingWestern Blottingalcohol effectalcohol sensitivityblood pressure regulationcatalasecaveolin 1clinically relevantenzyme activitygenetic regulatory proteinheme oxygenase-1interdisciplinary approachneurochemistrynormotensivenovelprogramsprotein expressionresponsesecond messenger
项目摘要
DESCRIPTION (provided by applicant): Alcohol elicits unique cardiovascular responses, which are not only dependent on the neuronal substrates within the brainstem but also on the genetic state of these neurons. The objective of this proposal is to elucidate the molecular mechanisms implicated in the differential effect of ethanol on specialized neurons in the brainstem that control blood pressure and cardiac reflexes in a model of essential hypertension, the spontaneously hypertensive rat (SHR). Our recent intriguing findings showed that site dependent neurochemical (norepinephrine, NE) and IEG gene/protein expression (c-jun/c-Jun) responses elicited by ethanol in the ventrolateral medulla (RVLM) and nucleus tractus solitarius (NTS) determine its divergent effects on blood pressure and baroreflex responses in hypertensive and normotensive rats. Given the altered cardiovascular neurobiology and neuronal sensitivity to ethanol in SHRs, we hypothesize that heme oxygenase (HO) derived carbon monoxide (CO) constitutes a novel molecular mechanism for the centra! cardiovascular effects of ethanol. To test this hypothesis, we propose a series of integrative, and molecular studies under three aims. Aim 1 establishes brainstem HO-CO pathway as a molecular mechanism for the divergent cardiovascular actions of ethanol in SHRs and WKY rats. Aim 2 will elucidate the effect of ethanol on the association of HO with its regulatory proteins caveolin-1 and calmodulin in brainstem neurons of SHRs and WKY rats. Aim 3 characterizes the role of HO-CO-MAPK pathway in ethanol-mediated cardiovascular responses. Since catalase activity (the major enzyme that metabolizes ethanol in the brain) is altered in SHRs, the potential contribution of acetaldehyde to ethanol actions will be investigated. The proposal adopts a well designed experimental approach that incorporates an established model system, appropriate controls and pharmacological and siRNA interventions to: (i) establish a causal relationship between inhibition of HO-derived CO and the sympathoexcitatory (pressor) and baroreflex depressant effects of ethanol, and (ii) identify the molecular mechanisms implicated in the site- and strain-dependent neurochemical and cardiovascular effects of ethanol. The proposed research whose primary focus is to probe the molecular mechanisms implicated in the adverse ethanol effects on cardiovascular neurobiology, addresses a significant biomedical problem and is expected to yield clinically relevant information.
描述(由申请人提供):酒精会引起独特的心血管反应,这不仅取决于脑干内的神经元底物,而且还取决于这些神经元的遗传状态。该建议的目的是阐明与乙醇对脑干中专业神经元差异作用有关的分子机制,该神经元在基本高血压模型(自发性高血压大鼠(SHR)的基本高血压模型中控制血压和心脏反射)。我们最近的有趣发现表明,乙醇在腹侧髓质(RVLM)(RVLM)和核Tractus solitarius(NTS)中引起的乙醇引起的依赖性神经化学(去甲肾上腺素,NE)和IEG基因/蛋白表达(C-JUN/C-JUN)反应,确定其对血液的影响和巴氏症的效应。考虑到SHR中对乙醇的心血管神经生物学和神经元敏感性的改变,我们假设血红素氧酶(HO)衍生的一氧化碳(CO)构成了Centra的新分子机制!乙醇的心血管效应。为了检验这一假设,我们提出了一系列以三个目标的综合性和分子研究。 AIM 1建立了脑干HO-CO途径,作为SHR和WKY大鼠乙醇发散心血管作用的分子机制。 AIM 2将阐明乙醇对HO与其调节蛋白的缔合可爱素-1和钙调蛋白在SHR和WKY大鼠的脑干神经元中的作用。 AIM 3表征了HO-CO-MAPK途径在乙醇介导的心血管反应中的作用。由于SHR中的过氧化氢酶活性(代谢乙醇代谢乙醇的主要酶)将在SHR中改变,因此将研究乙醛对乙醇作用的潜在贡献。该提案采用了精心设计的实验方法,该方法结合了既定的模型系统,适当的控制以及药理学和siRNA干预措施:(i)在抑制HODERED CO的抑制与交感神经(Perspor)(perspor)(perspor)之间建立因果关系,并确定乙醇的降压和(II)的分子效应,(II)确定了与分子的影响。乙醇。拟议的研究是,其主要重点是探测与乙醇对心血管神经生物学作用有关的分子机制,它解决了一个重大的生物医学问题,并有望产生与临床相关的信息。
项目成果
期刊论文数量(27)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Inhibition of nischarin expression attenuates rilmenidine-evoked hypotension and phosphorylated extracellular signal-regulated kinase 1/2 production in the rostral ventrolateral medulla of rats.
抑制尼沙林表达可减轻利美尼定引起的低血压和大鼠头端腹外侧延髓中磷酸化细胞外信号调节激酶 1/2 的产生。
- DOI:10.1124/jpet.107.129049
- 发表时间:2008
- 期刊:
- 影响因子:0
- 作者:Zhang,Jian;Abdel-Rahman,AbdelA
- 通讯作者:Abdel-Rahman,AbdelA
N-Methyl-D-Aspartate Receptor Signaling and Function in Cardiovascular Tissues.
- DOI:10.1097/fjc.0000000000000398
- 发表时间:2016-08
- 期刊:
- 影响因子:3
- 作者:McGee MA;Abdel-Rahman AA
- 通讯作者:Abdel-Rahman AA
Influence of sex on cardiovascular drug responses: role of estrogen.
- DOI:10.1016/j.coph.2017.02.002
- 发表时间:2017-04
- 期刊:
- 影响因子:4
- 作者:Abdel-Rahman AA
- 通讯作者:Abdel-Rahman AA
A pivotal role for enhanced brainstem Orexin receptor 1 signaling in the central cannabinoid receptor 1-mediated pressor response in conscious rats.
- DOI:10.1016/j.brainres.2015.06.011
- 发表时间:2015-10-05
- 期刊:
- 影响因子:2.9
- 作者:Ibrahim BM;Abdel-Rahman AA
- 通讯作者:Abdel-Rahman AA
Role of rostral ventrolateral medullary ERK/JNK/p38 MAPK signaling in the pressor effects of ethanol and its oxidative product acetaldehyde.
- DOI:10.1111/acer.12179
- 发表时间:2013-11
- 期刊:
- 影响因子:0
- 作者:El-Mas MM;Fan M;Abdel-Rahman AA
- 通讯作者:Abdel-Rahman AA
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{{ truncateString('ABDEL A ABDEL-RAHMAN', 18)}}的其他基金
Negative Impact of Alcohol on Cardiovascular Neurobiology
酒精对心血管神经生物学的负面影响
- 批准号:
8135112 - 财政年份:2010
- 资助金额:
$ 45.31万 - 项目类别:
Mechanisms of Alcohol-Estrogen Hemodynamic Interaction
酒精-雌激素血流动力学相互作用的机制
- 批准号:
7387487 - 财政年份:2004
- 资助金额:
$ 45.31万 - 项目类别:
Mechanisms For Estrogen-Dependent Myocardial Depressant Effect Of Ethanol
乙醇雌激素依赖性心肌抑制作用的机制
- 批准号:
8131991 - 财政年份:2004
- 资助金额:
$ 45.31万 - 项目类别:
Mechanisms For Estrogen-Dependent Myocardial Depressant Effect Of Ethanol
乙醇雌激素依赖性心肌抑制作用的机制
- 批准号:
8693868 - 财政年份:2004
- 资助金额:
$ 45.31万 - 项目类别:
Sex/estrogen-dependent vulnerability to alcohol-evoked cardiotoxicity: Role of circadian rhythm regulated enzymes
性别/雌激素依赖性酒精诱发心脏毒性的脆弱性:昼夜节律调节酶的作用
- 批准号:
10223099 - 财政年份:2004
- 资助金额:
$ 45.31万 - 项目类别:
Sex/estrogen-dependent vulnerability to alcohol-evoked cardiotoxicity: Role of circadian rhythm regulated enzymes
性别/雌激素依赖性酒精诱发心脏毒性的脆弱性:昼夜节律调节酶的作用
- 批准号:
10455478 - 财政年份:2004
- 资助金额:
$ 45.31万 - 项目类别:
Mechanisms of Alcohol-Estrogen Hemodynamic Interaction
酒精-雌激素血流动力学相互作用的机制
- 批准号:
6891041 - 财政年份:2004
- 资助金额:
$ 45.31万 - 项目类别:
Mechanisms of Alcohol-Estrogen Hemodynamic Interaction
酒精-雌激素血流动力学相互作用的机制
- 批准号:
7174843 - 财政年份:2004
- 资助金额:
$ 45.31万 - 项目类别:
Mechanisms of Alcohol-Estrogen Hemodynamic Interaction
酒精-雌激素血流动力学相互作用的机制
- 批准号:
6770603 - 财政年份:2004
- 资助金额:
$ 45.31万 - 项目类别:
Sex/estrogen-dependent vulnerability to alcohol-evoked cardiotoxicity: Role of circadian rhythm regulated enzymes
性别/雌激素依赖性酒精诱发心脏毒性的脆弱性:昼夜节律调节酶的作用
- 批准号:
9769595 - 财政年份:2004
- 资助金额:
$ 45.31万 - 项目类别:
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急性乙醇后肝线粒体呼吸激活、去极化和恢复
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Hepatic Mitochondrial Respiratory Activation, Depolarization and Recovery After Acute Ethanol
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The role of PDK4 in alcohol-associated liver disease
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