Neurotrophins and post-infarct plasticity in cardiac sympathetic neurons

项目摘要 在美国，冠心病是主要的死亡原因，而存活于冠状动脉的患者 闭塞有发生心律失常和心脏性猝死的高风险。的空间异质性 交感神经传递是脑梗塞后心律失常和心源性猝死的主要因素 在人类研究中，心肌梗死(MI)和交感神经丧失可预测心律失常的风险。在.期间 在之前的支持期中，我们发现持续性失神经是由硫酸软骨素引起的 瘢痕中的蛋白多糖作用于神经元蛋白酪氨酸磷酸酶受体SIGMA(PtPσ)。 使用遗传学或治疗性肽isp靶向ptpσ可促进神经再支配。删除ptpσ 标准化的心肌细胞β-AR信号、心脏电生理学和心肌细胞钙处理，呈现心脏 抵抗异丙肾上腺素引起的心律失常。我们假设这是神经再支配，而不是缺乏ptpσ， 使心肌梗死后的心脏电生理和钙离子处理正常化。我们将用两个例子来检验这一假设 修复心脏神经的治疗方法：靶向ptpσ的isp和结合的新小分子(HJ-2) TrkA。这将使我们能够区分由这两种药物刺激的再神经支配的效果。 药物特有的影响。我们将确定神经再支配是否使心脏电生理和钙离子正常化 处理，如果再神经和它的影响是持续的，如果需要去甲肾上腺素传递 恢复心脏的电稳定。我们将确定在瘢痕成熟过程中是否有交感神经再支配 增强心脏修复或改变炎症反应，如果延迟再神经支配具有保护作用。我们 汇集了一支优秀的专家团队，以及新型化学试剂和成像工具，以 协助我们完成这些研究。这项工作将测试用疗法刺激神经再生是否可以 使心脏电生理正常化，减少心律失常，并将确定涉及的机制。

Project Summary Coronary heart disease is the leading cause of death in the U.S., and patients who survive a coronary artery occlusion have a high risk for cardiac arrhythmias and sudden cardiac death. Spatial heterogeneity of sympathetic transmission is a major contributor to post-infarct arrhythmias and sudden cardiac death after myocardial infarction (MI), and sympathetic denervation predicts arrhythmia risk in human studies. During the previous period of support we discovered that persistent denervation was caused by chondroitin sulfate proteoglycans (CSPGs) in the scar acting on neuronal Protein Tyrosine Phosphatase Receptor Sigma (PTPσ). Targeting PTPσ using genetics or the therapeutic peptide ISP promoted reinnervation. Deletion of PTPσ normalized myocyte β-AR signaling, cardiac electrophysiology, and myocyte Ca2+ handling, rendering hearts resistant to isoproterenol-induced arrhythmias. We hypothesize that it is reinnervation, not the lack of PTPσ, which normalizes cardiac electrophysiology and Ca2+ handling after MI. We will test that hypothesis using two therapeutics to restore cardiac nerves: ISP which targets PTPσ, and a novel small molecule (HJ-2) which binds TrkA. This will allow us to distinguish the effects of reinnervation, which is stimulated by both drugs, from other drug-specific effects. We will determine if reinnervation normalizes cardiac electrophysiology and Ca2+ handling, if reinnervation and its effects are sustained, and if noradrenergic transmission is required for restoring electrical stability in the heart. We will determine if sympathetic reinnervation during scar maturation enhances cardiac repair or alters the inflammatory response, and if delayed reinnervation is protective. We have assembled an outstanding team of experts along with novel chemical reagents and imaging tools to assist us in completing these studies. This work will test if stimulating nerve regeneration with therapeutics can normalize cardiac electrophysiology and decrease arrhythmias, and will identify the mechanisms involved.