Neurotrophins and Post-infarct Plasicity in Cardiac Sympathetic Neurons

描述(申请人提供)：心肌梗死改变心脏中的交感神经传递，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，在美国每年造成约30万人死亡。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。脑梗塞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，因为细胞外去甲肾上腺素(NE)随着神经细胞表达甘丙肽和PACAP(垂体腺苷环化酶激活多肽)而增加。第二，在最初的损伤后不久，存活的梗死灶周围心肌中的轴突退化，然后异质性地重新生长，导致局部过度神经支配。这一应用将检验这一假说，即梗塞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。神经营养因子神经生长因子(NGF)和脑源性神经营养因子(BDNF)在心肌梗死后升高。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，p75的BDNF激活刺激轴突变性，而TrkA的NGF激活导致心脏交感神经元轴突生长和神经肽表达增加。TrkAF592a小鼠的最新发展为测试TrkA功能在交感神经系统完整的成年动物中的作用提供了新的机会。因此，我们将利用遗传模型在体内操纵神经营养因子信号，并剖析p75和TrkA在脑梗塞后交感神经失调中的作用，包括：1)去神经支配，2)高神经支配，3)神经肽产生，4)NE合成和更新，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。这一研究计划将促进我们对心肌梗死后交感神经病变的分子基础的理解，并可能促进新的治疗方法的靶向开发。公共卫生相关性：心肌梗死会改变心脏中的交感神经传递，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，这是主要的死亡原因。这些研究将确定调节心肌梗死后交感神经传递病理变化的关键因素，并可能导致开发治疗心肌梗死的新治疗策略。

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.