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: 7743299
• 负责人: BETH A HABECKER
• 金额: $ 38.1万
• 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/7743299
• 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; public health relevance; receptor; research study; response; sudden cardiac death; transcriptional coactivator p75; transmission process

DESCRIPTION (provided by applicant): 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 application 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. PUBLIC HEALTH RELEVANCE: 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 are leading causes of death in the U.S. These studies will identify key factors regulating the pathological changes in sympathetic transmission after infarction, and may lead to the development of new therapeutic strategies in the treatment of myocardial infarction.

描述（由申请人提供）：心肌梗死改变了心脏中的交感神经传递，交感神经功能障碍是梗死后室性心律失常和心脏性猝死的主要原因，在美国每年约有300，000人死亡。拟议研究的长期目标是了解心肌梗死后交感神经传递改变的分子基础。心肌梗死触发心脏交感神经元的两种可塑性。首先是关键的神经递质和神经肽变化，因为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）的神经元表达一起增加。第二，在最初损伤后不久，存活的梗死周围心肌中的轴突退化，然后不均匀地重新生长，导致区域性神经支配过度。这个应用程序将测试的假设，即梗死诱导的神经营养因子的神经化学和轴突可塑性心脏交感神经元中看到的关键。脑梗死后心脏中神经营养因子神经生长因子（NGF）和脑源性神经营养因子（BDNF）升高。神经营养因子通过TrkA酪氨酸激酶受体和p75受体两种受体对交感神经元发挥作用。我们的初步数据表明，BDNF激活p75刺激轴突变性，而NGF激活TrkA导致轴突生长和增加心脏交感神经元中的神经肽表达。TrkAF592A小鼠的最新发展提供了一个新的机会来测试TrkA功能在具有完整交感神经系统的成年动物中的作用。因此，我们将使用遗传模型来操纵体内神经营养因子信号传导，并剖析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）对心律失常的易感性和心脏功能的控制。为了补充整个动物研究，我们将在培养的心脏交感神经元中进行额外的实验，以确定控制轴突大小，神经肽合成或神经递质产生的特定细胞内信号通路。这项研究计划将促进我们对梗死后心脏交感神经支配病理变化的分子基础的理解，并可能促进新疗法的靶向开发。公共卫生相关性：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导致梗死后室性心律失常和心脏性猝死的主要因素，这是美国死亡的主要原因。这些研究将确定调节梗死后交感神经传递病理变化的关键因素，并可能导致新的治疗策略在心肌梗死治疗中的发展。