Neurotrophins and post-infarct plasticity in cardiac sympathetic neurons

神经营养素和心脏交感神经元的梗塞后可塑性

• 批准号: 8815711
• 负责人: BETH A HABECKER
• 金额: $ 41.66万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8815711
• 关键词: Adrenergic Fibers; American; Animal Model; Arrhythmia; Axon; Brain-Derived Neurotrophic Factor; Cardiac; Cardiac Electrophysiologic Techniques; Cardiac Myocytes; Cause of Death; Chondroitin Sulfate Proteoglycan; Cicatrix; Clinical Trials; Coronary heart disease; Coupling; Data; Denervation; Development; Electrocardiogram; Frequencies; Genetic; Heart; Heterogeneity; Human; Infarction; Intervention; Left; Left ventricular structure; Ligands; Location; Maps; Methods; Molecular; Muscle Cells; Myocardial Infarction; Myocardium; NGFR Protein; Natural regeneration; Nerve; Nerve Growth Factors; Nerve Regeneration; Neurons; Optics; Patients; Phosphoric Monoester Hydrolases; Predisposition; Resistance; Risk; Sympathectomy; Sympathetic Nerve Block; Telemetry; Testing; Therapeutic; Time; Ventricular Arrhythmia; Wild Type Mouse; Work; axon growth; axon regeneration; base; coronary artery occlusion; electrical property; genetic approach; high risk; human PTPRT protein; nerve supply; neurotrophic factor; novel; prevent; public health relevance; receptor; reinnervation; reuptake; sudden cardiac death; therapeutic development; tool; transcriptional coactivator p75; transmission process

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.

描述（由申请人提供）：冠心病是美国的主要死亡原因，并且在冠状动脉阻塞中存活的患者具有心律失常和心源性猝死的高风险。交感神经传导的空间异质性是心肌梗死（MI）后梗死后心律失常和心源性猝死的主要原因，在最近的人体研究中，交感神经去神经支配可预测心律失常风险。 我们已经确定了MI后两种不同类型的交感神经去神经：1）梗死/瘢痕和相邻边缘区肌细胞的持续去神经，和2）未受伤的梗死周围心肌的短暂去神经。该提案将开发预防或逆转这两种类型的去神经支配的方法，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。由于硫酸软骨素蛋白多糖（CSPGs），MI后梗死区仍然失神经支配。我们鉴定出蛋白酪氨酸磷酸酶受体σ（PTP β）是交感神经元中主要的CSPG受体，并发现去除PTP β会导致边缘区的神经再支配和心脏瘢痕的神经过度支配。初步数据表明，消除PTP使心脏电生理正常化，并使心脏对MI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具有有益的影响。然而，目前尚不清楚神经再支配是否是预防心律失常的关键，或者PTP的其他作用是否会降低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的相互作用来防止神经再支配（目的1），而恢复交感神经支配将降低心律失常的易感性（目的2）。梗死周围心肌在MI后1天和3天短暂去神经支配，梗死外交感神经纤维的丧失需要p75神经营养因子受体的激活。我们鉴定了ProNGF和一种形式的脑源性神经营养因子（proBDNF或BDNF）作为MI后心脏中升高的p75配体。我们将检验前神经营养因子和/或BDNF刺激梗死周围去神经支配，以及预防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）。 我们已经组建了一个杰出的专家团队，沿着有独特的动物模型和新颖的遗传工具，以帮助我们完成这些研究。这项工作将直接测试MI后操纵心脏神经是否可以使心脏电生理正常化并减少心律失常频率，为治疗开发开辟新的途径。