Negative Impact of Alcohol on Cardiovascular Neurobiology

描述（由申请人提供）：酒精引起独特的心血管反应，这不仅取决于脑干内的神经元基质，而且还取决于这些神经元的遗传状态。本提案的目的是阐明乙醇对脑干中控制血压和心脏反射的特化神经元的差异效应中所涉及的分子机制，所述脑干中的特化神经元在原发性高血压模型，自发性高血压大鼠（SHR）中。我们最近有趣的研究结果表明，在高血压和正常血压大鼠中，乙醇在延髓腹外侧区（RVLM）和孤束核（NTS）引起的部位依赖性神经化学（去甲肾上腺素，NE）和IEG基因/蛋白表达（c-Jun/c-Jun）反应决定了其对血压和压力反射反应的不同影响。考虑到自发性高血压大鼠心血管神经生物学和神经元对乙醇的敏感性改变，我们假设血红素加氧酶（HO）衍生的一氧化碳（CO）构成了中枢神经系统的一种新的分子机制。乙醇对心血管的影响为了验证这一假设，我们提出了一系列的综合，和分子研究下三个目标。目的1建立乙醇对自发性高血压大鼠和WKY大鼠心血管作用差异的分子机制。目的2探讨乙醇对自发性高血压大鼠和WKY大鼠脑干神经元HO与其调节蛋白caveolin-1和钙调素（calmodulin）的关系。目的3探讨HO-CO-MAPK通路在乙醇介导的心血管反应中的作用。由于过氧化氢酶活性（大脑中代谢乙醇的主要酶）在SHR中发生改变，因此将研究乙醛对乙醇作用的潜在贡献。该提案采用了一种设计良好的实验方法，该方法结合了已建立的模型系统、适当的对照以及药理学和siRNA干预，以：（i）建立HO衍生的CO的抑制与乙醇的交感神经兴奋（升压）和压力反射抑制效应之间的因果关系，和（ii）确定乙醇的位点依赖性和应变依赖性神经化学和心血管效应中涉及的分子机制。拟议的研究，其主要重点是探索在不良乙醇对心血管神经生物学的影响牵连的分子机制，解决了一个重要的生物医学问题，并预计产生临床相关的信息。

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.