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Dysfunction of Baroreceptor Neurons in Heart Failure: Cellular and Molecular Mech

心力衰竭中压力感受器神经元的功能障碍：细胞和分子机制

基本信息

批准号：
8495401
负责人：
Yu-Long Li
金额：
$ 34.99万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8495401
关键词：
Action Potentials Affect Angiotensin II Animals Attenuated Baroreflex Binding Canis familiaris Cell physiology Cells Cellular Membrane Chronic Clinical Complementary DNA Complex Complication Copper Cytosol Data Depressed mood Fiber Functional disorder Ganglia Genomics Heart failure Impairment In Vitro Ion Channel Kinetics Limb structure Manganese Superoxide Dismutase Mediating Mental Depression Messenger RNA Mitochondria Modeling Molecular Multienzyme Complexes Myocardial Infarction NADPH Oxidase NF-kappa B Nerve Neurons Nodose Ganglion Patients Pressoreceptors Production Property Protein Isoforms Proteins Rattus Receptor, Angiotensin, Type 1 Reflex action Research Design Role Sensory Signal Transduction Small Interfering RNA Sodium Sodium Channel Staining method Stains Superoxides Survival Rate System Techniques Testing Time Tissues Transfection Transgenes Western Blotting Zinc base chromatin immunoprecipitation copper zinc superoxide dismutase enzyme activity improved in vivo mitochondrial dysfunction mortality neuronal cell body outcome forecast overexpression patch clamp pressure promoter protein expression public health relevance receptor receptor expression research study sham surgery therapeutic target transcription factor voltage

项目摘要

DESCRIPTION (provided by applicant): Clinical and animal studies have confirmed a contribution of arterial baroreflex impairment to the prognosis and mortality of chronic heart failure (CHF). However, the mechanisms underlying baroreflex dysfunction remain unclear. As the primary component of the baroreflex, the afferent limb comprised of arterial baroreceptor (AB) neurons is involved in the attenuated baroreflex sensitivity in the CHF state. It is well known that the pressure sensitivity of these baroreceptor neurons is blunted in CHF. This blunted sensitivity generally has been assumed to result from an impairment of mechanotransduction at the sensory terminals. However, changes in the electrical (cable) properties of the cellular membrane of baroreceptor neurons also may contribute to suppressed excitability. Based upon our preliminary data, we hypothesize that reduced expression and activation of voltage-gated sodium (Nav) channels contributes to the depressed AB neuron excitability and blunted aortic arterial baroreflex sensitivity in CHF. We further hypothesize that angiotensin II (AngII)- superoxide signaling mediates these changes in Nav channel function. In order to test this hypothesis, we propose to perform in vivo and in vitro studies at the whole animal (aortic arterial baroreflex), cellular (action potential and Nav channel recording in AB neurons), and molecular (mRNA/protein expression, nuclear factor-kappa B binding to Nav channel promoter, siRNA, and adenoviral cDNA transfection) studies in sham and myocardial infarction-induced CHF rats. In Specific Aim 1, we will examine the relationship among CHF-induced alterations in Nav currents and excitability in AB neurons and aortic baroreflex sensitivity. In Specific Aim 2, we propose that endogenous superoxide over-production mediates these alterations by impairing AB neuron Nav channel activity, and through nuclear factor-kappa B suppression of Nav channel expression in CHF rats. Finally, we propose in Specific Aim 3 that elevation of AngII and over-expression of the AngII type 1 receptors occur in CHF rat nodose ganglia and mediate the superoxide over-production via NADPH oxidase and mitochondrial dysfunction and subsequently affect Nav channel function, neuron excitability, and aortic baroreflex sensitivity in CHF rats. Taken together, these studies will provide new information on the mechanisms underlying the impaired baroreflex in CHF and will also unveil important pharmacological and genomic targets for improving baroreflex function and reducing mortality in CHF.

描述(申请人提供)：临床和动物研究已证实动脉压力感受性反射障碍对慢性心力衰竭(CHF)的预后和死亡率有一定影响。然而，压力感受性反射功能障碍的机制仍不清楚。作为压力感受性反射的主要组成部分，由动脉压力感受器(AB)神经元组成的传入肢参与了CHF状态下压力感受性反射敏感性的减弱。众所周知，这些压力感受器神经元的压力敏感性在充血性心力衰竭时被钝化。这种钝化的敏感性通常被认为是感觉神经末端机械转导功能受损的结果。然而，压力感受器神经元细胞膜的电(电缆)特性的变化也可能有助于抑制兴奋性。根据我们的初步数据，我们假设，电压门控钠(NAV)通道表达和激活的减少与CHF时AB神经元兴奋性降低和主动脉压力感受器反射敏感性钝化有关。我们进一步假设，血管紧张素II(AngII)-超氧化物信号介导了NAV通道功能的这些变化。为了验证这一假说，我们建议对假手术和心肌梗死诱导的CHF大鼠进行整体动物(主动脉压力感受器反射)、细胞(AB神经元的动作电位和NAV通道记录)和分子(mRNA/蛋白表达、核因子-kappa B与NAV通道启动子结合、siRNA和腺病毒c DNA转染)的体内和体外研究。在具体目标1中，我们将研究CHF引起的NAV电流改变和AB神经元兴奋性与主动脉压力感受器反射敏感性之间的关系。在特定的目标2中，我们认为内源性超氧阴离子过量产生通过损害AB神经元NAV通道活性和通过核因子-kappa B抑制CHF大鼠NAV通道的表达来介导这些改变。最后，我们在特定的目标3中提出，CHF大鼠结状神经节中存在AngII升高和AngII 1型受体的过度表达，并通过NADPH氧化酶和线粒体功能障碍介导超氧化物歧化，从而影响NAV通道功能、神经元兴奋性和主动脉压力感受性反射敏感性。综上所述，这些研究将为CHF压力反射受损的机制提供新的信息，还将揭示改善CHF压力反射功能和降低死亡率的重要药理学和基因组靶点。