Neurotrophins and Post-infarct Plasicity in Cardiac Sympathetic Neurons

项目摘要 心肌梗死改变了心脏中的交感神经传递，而交感神经功能障碍是主要的 导致心梗后室性心律失常和心脏性猝死，在美国每年造成约30万人死亡。 这项拟议研究的长期目标是了解交感神经改变的分子基础。 心肌梗死后的传播。脑梗塞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) 伴随着神经细胞甘丙肽和PACAP(垂体腺苷环化酶)的表达增加。 活化多肽)。第二，在最初的梗死灶周围存活的心肌组织中，轴突很快退化。 损伤后异质再生长，导致局部超神经支配。这项提案将考验 脑梗塞诱导的神经营养因子对神经化学和轴突可塑性至关重要的假说 心脏交感神经元。神经营养因子神经生长因子与脑源性神经营养 心肌梗死后心脏组织中的脑源性神经营养因子(BDNF)升高。神经营养因子在交感神经中发挥作用 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 心脏交感神经元生长和神经肽表达增加。的最新发展 TrkAF592A小鼠为测试TrkA功能在成年动物中的作用提供了一个新的机会 交感神经系统。因此，我们将使用遗传模型来操纵神经营养素信号转导 P75和TrkA在脑梗塞后交感神经调节障碍中的作用，包括：1) 去神经，2)超神经支配，3)神经肽的产生，4)NE的合成和更新，5) 对心律失常的敏感性和心功能的控制。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识别特定的细胞内 对控制轴突大小、神经肽合成或神经递质产生至关重要的信号通路。 这项研究计划将促进我们对脑血管病变的分子基础的理解。 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开发。

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.