Neurotrophins and Post-infarct Plasicity in Cardiac Sympathetic Neurons

描述（由申请人提供）：心肌梗死改变了心脏的交感神经传递，而交感神经功能障碍是梗死后室性心律失常和心源性猝死的主要原因，在美国每年约有30万人因此死亡。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。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的变化，如细胞外去甲肾上腺素（NE）与肽丙氨酸和PACAP（垂体腺苷酸环化酶激活多肽）的神经元表达一起增加。其次，在初始损伤后不久，存活的梗死周围心肌的轴突退化，然后异质再生，导致局部神经过度支配。该应用将验证梗死诱导的神经营养因子对心脏交感神经元的神经化学和轴突可塑性至关重要的假设。心肌梗死后，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受体两种受体作用于交感神经元。我们的初步数据表明，BDNF激活p75刺激轴突变性，而NGF激活TrkA导致轴突生长和心脏交感神经元神经肽表达增加。最近TrkAF592A小鼠的发展为在具有完整交感神经系统的成年动物中测试TrkA功能的作用提供了新的机会。因此，我们将使用遗传模型在体内操纵神经营养因子信号，并解剖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)神经过度支配，3)神经肽产生，4)NE合成和转换，以及5)心律失常易感性和心功能控制。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，以确定对控制轴突大小、神经肽合成或神经递质产生至关重要的特定细胞内信号通路。该研究计划将促进我们对梗死后心脏交感神经病理改变的分子基础的理解，并可能促进新疗法的靶向开发。公共卫生相关性：心肌梗死改变心脏的交感神经传递，而交感神经功能障碍是梗死后室性心律失常和心源性猝死的主要原因，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，并可能导致心肌梗死治疗的新治疗策略的发展。

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.