Neurotrophins and post-infarct plasticity in cardiac sympathetic neurons

项目摘要 冠心病是美国的主要死因，以及冠状动脉破裂后 闭塞具有心律失常和心源性猝死的高风险。空间异质性 交感神经传递是心肌梗死后心律失常和心脏性猝死的主要原因， 心肌梗死（MI）和交感神经去神经预测心律失常的风险在人类研究。期间 在前一个支持阶段，我们发现持续性去神经是由硫酸软骨素引起的， 瘢痕中的蛋白聚糖（CSPG）作用于神经元蛋白酪氨酸磷酸酶受体σ（PTPσ）。 使用遗传学或治疗肽ISP靶向PTPσ促进神经再支配。删除PTPσ 正常化的肌细胞β-AR信号传导、心脏电生理学和肌细胞Ca 2+处理， 对异丙肾上腺素诱发的心律失常有抵抗力我们假设这是神经再支配，而不是缺乏PTPσ， 其使MI后的心脏电生理学和Ca 2+处理正常化。我们将使用两个 恢复心脏神经的治疗：靶向PTPσ的ISP和一种新的小分子（HJ-2）， TrkA。这将使我们能够区分神经再生的影响，这是由两种药物刺激，从其他 药物特异性效应。我们将确定神经再支配是否使心脏电生理和Ca 2+正常化， 处理，如果神经再支配及其影响持续，如果需要去甲肾上腺素能传递， 恢复心脏的电稳定性我们将确定在疤痕成熟过程中交感神经的再支配 增强心脏修复或改变炎症反应，以及延迟神经再支配是否具有保护作用。我们 我们已经组建了一支优秀的专家团队，沿着，并配备了新型化学试剂和成像工具， 帮助我们完成这些研究。这项工作将测试用治疗剂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，并将确定相关的机制。

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.