Neurotrophins and Post-infarct Plasicity in Cardiac Sympathetic Neurons

神经营养素和心脏交感神经元梗死后的柔软性

• 批准号: 8257569
• 负责人: BETH A HABECKER
• 金额: $ 37.69万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257569
• 关键词: Address; Adrenergic Fibers; Adult; Animals; Arrhythmia; Axon; Brain-Derived Neurotrophic Factor; Cardiac; Cardiac Myocytes; Cause of Death; Complement; Complex; Data; Denervation; Development; Electrocardiogram; Functional disorder; Galanin; Generations; Genetic Models; Goals; Heart; Heart Atrium; In Vitro; Infarction; Injury; Ischemia; Lead; Measures; Molecular; Mus; Myocardial Infarction; Myocardium; Nerve; Nerve Growth Factors; Neuronal Plasticity; Neurons; Neuropeptides; Neurotransmitters; Neurotrophic Tyrosine Kinase Receptor Type 1; Norepinephrine; Operative Surgical Procedures; Peptides; Predisposition; Production; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Reperfusion Therapy; Research; Risk Factors; Role; Shapes; Signal Pathway; Signal Transduction; Structure; Sympathetic Nervous System; Testing; Tissues; Tyrosine 3-Monooxygenase; Ventricular Arrhythmia; base; chemical genetics; extracellular; heart innervation; heart rhythm; in vitro activity; in vivo; inhibitor/antagonist; killings; mature animal; nerve supply; neurochemistry; neurotrophic factor; novel; novel therapeutics; pituitary adenylate cyclase activating polypeptide; receptor; research study; response; sudden cardiac death; transcriptional coactivator p75; transmission process

Project Summary Myocardial infarction alters sympathetic transmission in the heart, and sympathetic dysfunction is a major contributor to post-infarct ventricular arrhythmia and sudden cardiac death, which kill ~300,000/year in the U.S. The long term goal of the proposed research is to understand the molecular basis for altered sympathetic transmission following myocardial infarction. Infarction triggers two types of plasticity in cardiac sympathetic neurons. First are key neurotransmitter and neuropeptide changes, as extracellular norepinephrine (NE) increases together with neuronal expression of the peptides galanin and PACAP (pituitary adenylate cyclase- activating polypeptides). Second, axons degenerate in the viable peri-infarct myocardium soon after the initial injury and then re-grow heterogeneously leading to regional hyperinnervation. This proposal will test the hypothesis that infarction-induced neurotrophins are critical for the neurochemical and axonal plasticity seen in cardiac sympathetic neurons. The neurotrophins Nerve Growth Factor (NGF) and Brain Derived-Neurotrophic Factor (BDNF) are elevated in heart following infarction. Neurotrophins exert their effects on sympathetic neurons through two receptors, the TrkA tyrosine kinase receptor and the p75 receptor. Our preliminary data suggest that BDNF activation of p75 stimulates axon degeneration, while NGF activation of TrkA leads to axon outgrowth and increased neuropeptide expression in cardiac sympathetic neurons. The recent development of TrkAF592A mice offers a new opportunity to test the role of TrkA function in adult animals that have an intact sympathetic nervous system. Therefore, we will use genetic models to manipulate neurotrophin signaling in vivo and dissect the contributions of p75 and TrkA in post-infarct sympathetic dysregulation, including: 1) denervation, 2) hyper-innervation, 3) neuropeptide production, 4) NE synthesis and turnover, and 5) susceptibility to arrhythmias and control of cardiac function. To complement the whole animal studies we will carry out additional experiments in cultured cardiac sympathetic neurons to identify specific intracellular signaling pathways critical for control of axon size, neuropeptide synthesis, or neurotransmitter production. This research plan will advance our understanding of the molecular basis for pathological changes in the cardiac sympathetic innervation after infarction, and may facilitate targeted development of novel therapeutics.

项目摘要 心肌梗死改变了心脏的交感神经传递，交感神经功能障碍是心肌梗死的主要原因。 导致梗死后室性心律失常和心源性猝死，在美国每年约有30万人死亡。 这项研究的长期目标是了解交感神经系统改变的分子基础。 心肌梗塞后的传导。心肌梗死触发心脏交感神经的两种可塑性 神经元首先是关键的神经递质和神经肽的变化，如细胞外去甲肾上腺素（NE） 与肽甘丙肽和PACAP（垂体腺苷酸环化酶， 激活多肽）。第二，轴突退化后不久，在存活的梗死周围心肌的初始 损伤，然后不均匀地重新生长，导致局部神经支配过度。这项提案将考验 假设梗死诱导的神经营养因子对神经化学和轴突可塑性至关重要， 心脏交感神经元。神经生长因子（NGF）与脑源性神经营养因子 脑梗死后心脏组织中BDNF水平升高。神经营养素发挥其作用， 神经元通过两种受体，TrkA酪氨酸激酶受体和p75受体。我们的初步数据 提示p75的BDNF激活刺激轴突变性，而TrkA的NGF激活导致轴突变性。 心脏交感神经元的生长和增加的神经肽表达。的最新发展 TrkAF 592A小鼠提供了一个新的机会来测试TrkA功能在具有完整的 交感神经系统因此，我们将使用遗传模型来操纵神经营养因子信号， 活体解剖分析p75和TrkA在梗死后交感神经失调中的作用，包括：1） 去神经支配，2）过度神经支配，3）神经肽产生，4）NE合成和周转，以及5） 易患心律失常和控制心脏功能。为了补充整个动物研究， 在培养的心脏交感神经元中进行额外的实验以鉴定特定的细胞内 信号传导通路对于控制轴突大小、神经肽合成或神经递质产生至关重要。 这项研究计划将促进我们对肿瘤病理变化的分子基础的理解， 心肌梗死后的心脏交感神经支配，并可能促进新疗法的靶向发展。