Neurotrophins and post-infarct plasticity in cardiac sympathetic neurons

描述（由申请人提供）：冠心病是美国死亡的主要原因，冠状动脉闭塞后存活的患者发生心律失常和心源性猝死的风险很高。交感神经传导的空间异质性是梗死后心律失常和心肌梗死（MI）后心源性猝死的主要因素，在最近的人体研究中，交感神经去支配预测心律失常的风险。我们已经确定了心肌梗死后两种不同类型的交感神经去支配：1)梗死/疤痕和邻近边界区肌细胞的持续性去支配，以及2)未损伤的梗死周围心肌的短暂性去支配。该建议将开发方法来预防或逆转这两种类型的去神经支配，并确定恢复整个心室的交感神经支配是否会降低心律失常的易感性。心肌梗死后，由于硫酸软骨素蛋白聚糖（CSPGs）的作用，梗死灶仍处于失神经状态。我们发现蛋白酪氨酸磷酸酶受体（PTP）是交感神经元中主要的CSPG受体，并发现去除PTP可导致心脏瘢痕边缘区神经再支配和神经过度支配。初步数据表明，消除PTP -使心脏电生理正常化，并使心脏对心肌梗死后心律失常具有惊人的抵抗力。这表明恢复交感神经支配对心律失常易感性有有益的作用。然而，尚不清楚是否再神经支配是预防心律失常的关键，或者是否PTP -的其他作用有助于降低PTP -心脏的心律失常易感性。我们假设PTP的主要作用是通过与CSPGs的相互作用来阻止神经再支配（Aim 1），而恢复交感神经支配将降低心律失常的易感性（Aim 2）。心肌梗死后1至3天，梗死周围心肌短暂失神经，梗死区外交感神经纤维的丧失需要激活p75神经营养因子受体。我们发现ProNGF和一种形式的脑源性神经营养因子（proBDNF或BDNF）是心肌梗死后心脏中升高的p75配体。我们将验证前神经营养因子和/或BDNF刺激梗死周围去神经支配的假设，以及防止梗死周围去神经支配将降低心律失常易感性的假设（目的3）。我们已经组建了一支优秀的专家团队，以及独特的动物模型和新颖的遗传工具来帮助我们完成这些研究。这项工作将直接检验心肌梗死后操纵心脏神经是否能使心电生理正常化，降低心律失常频率，为治疗发展开辟新的途径。

DESCRIPTION (provided by applicant): 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 predicted arrhythmia risk in recent human studies. We have identified two distinct types of sympathetic denervation after MI: 1) persistent denervation of the infarct/scar and adjacent border zone myocytes, and 2) transient denervation of uninjured peri-infarct myocardium. This proposal will develop methods to prevent or reverse both types of denervation, and determine if restoring sympathetic innervation throughout the ventricle decreases arrhythmia susceptibility. The infarct remains denervated after MI due to chondroitin sulfate proteoglycans (CSPGs). We identified protein tyrosine phosphatase receptor sigma (PTP�as the major CSPG receptor in sympathetic neurons, and found that removing PTP�esulted in reinnervation of the border zone and hyperinnervation of the cardiac scar. Preliminary data suggest that eliminating PTP�ormalizes cardiac electrophysiology and renders hearts surprisingly resistant to post-MI arrhythmias. This suggests that restoring sympathetic innervation has a beneficial effect on arrhythmia susceptibility. However, it's not clear if re-innervation is the key to preventing arrhythmias, or if other actions of PTP�ontribut to decreased arrhythmia susceptibility in PTP�- hearts. We hypothesize that the major action of PTP�s to prevent reinnervation via interactions with CSPGs (Aim 1), and that restoring sympathetic innervation will decrease arrhythmia susceptibility (Aim 2). Peri-infarct myocardium is transiently denervated 1 and 3 days after MI and loss of sympathetic fibers outside the infarct requires activation of the p75 neurotrophin receptor. We identified ProNGF and a form of Brain Derived Neurotrophic Factor (either proBDNF or BDNF) as p75 ligands that are elevated in the heart after MI. We will test the hypothesis that pro-neurotrophins and/or BDNF stimulate peri-infarct denervation, and that preventing peri- infarct denervation will decrease arrhythmia susceptibility (Aim 3). We have assembled an outstanding team of experts along with unique animal models and novel genetic tools to assist us in completing these studies. This work will test directly if manipulating cardiac nerves after MI can normalize cardiac electrophysiology and decrease arrhythmia frequency, opening a new avenue for therapeutic development.