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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

基本信息

批准号：
8463590
负责人：
BETH A HABECKER
金额：
$ 35.87万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2014-11-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8463590
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

项目摘要

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.

项目总结