Understanding the role of chondroitin sulfate proteoglycan 4-sulfation in the heart following myocardial infarction

了解硫酸软骨素蛋白多糖 4-硫酸化在心肌梗塞后心脏中的作用

• 批准号: 10186468
• 负责人: Matthew Russell Blake
• 金额: $ 4.6万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-16 至 2022-04-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186468
• 关键词: Affect; Animals; Area; Arrhythmia; Axon; Back; Calcium; Cardiac; Cardiac Electrophysiologic Techniques; Cause of Death; Cells; Chondroitin ABC Lyase; Chondroitin Sulfate A; Chondroitin Sulfate Proteoglycan; Cicatrix; Core Protein; Denervation; Electrocardiogram; Enzymes; Excision; Family; Fluorescence Resonance Energy Transfer; Glycosaminoglycans; Goals; Growth; Heart; Heart Block; Heart failure; Heterogeneity; Laminin; Lead; Microscopy; Molecular; Monitor; Myocardial Infarction; Myocardium; Nerve; Nerve Growth Factors; Neuraxis; Neurons; PC12 Cells; Pathway interactions; Patients; Pattern; Phosphotransferases; Predisposition; Protein Tyrosine Phosphatase; Rattus; Receptor Activation; Research; Risk; Role; Side; Signal Pathway; Signal Transduction; Signaling Protein; Small Interfering RNA; Sulfate; Sympathectomy; Sympathetic Ganglia; Telemetry; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Tropomyosin; Viral Vector; Work; axon regeneration; base; cell type; design; experimental study; heart damage; heart innervation; imaging platform; in vivo; inhibitor/antagonist; live cell imaging; mouse model; nerve injury; nerve supply; neurotransmission; new therapeutic target; pericardial sac; prevent; programs; protein activation; receptor; reinnervation; response; screening; sudden cardiac death; therapeutically effective; tissue culture; vector

PROJECT SUMMARY Sudden cardiac failure from cardiac arrhythmias is a leading cause of death for patients who have suffered a myocardial infarction (MI). Heterogeneity in sympathetic neurotransmission to damaged areas of the heart is thought to generate these arrhythmias. Following an early period of denervation after MI, the damaged cardiac tissue, or cardiac scar, has the capacity to stimulate nerve reinnervation due to high amounts of secreted Nerve Growth Factor (NGF) which activates tropomyosin receptor kinase A (TrkA). Despite this, nerves do not grow back into the scar due to the presence of chondroitin sulfate proteoglycans (CSPGs), resulting in a patchwork of innervation and denervation throughout the heart. The resulting denervated tissue is unable to respond to sympathetic neurotransmission leading to a heterogeneous response that generates cardiac arrhythmias. Previous work in our lab demonstrated that blocking CSPG signaling in sympathetic nerves restores sympathetic innervation of the cardiac scar and reduces arrhythmia susceptibility after MI. Therapeutic interventions to block CSPG signaling and restore sympathetic innervation of the cardiac scar would be a viable strategy to reduce post-MI arrhythmias and risk of sudden cardiac death but therapeutic design is limited by our understanding of CSPG signaling. CSPGs are a diverse family of molecules composed of different core proteins modified by glycosaminoglycans (GAG) side chains that can be further modified by sulfation. Evidence from research in the central nervous system (CNS) suggests that inhibition of axon outgrowth occurs primarily via 4S-CSPGs following nerve injury. Despite the critical role of CSPGs in preventing reinnervation of the cardiac scar it is unknown whether 4S- CSPGs specifically inhibit sympathetic axon outgrowth. This study will provide a mechanistic understanding of how CSPG sulfation in the cardiac scar affects sympathetic denervation in our mouse model of MI using the enzyme Arasulfatase B which selectively degrades 4S-CSPGs. Furthermore, CSPG-sulfation-induced signaling studies focusing downstream of TrkA signaling networks will elucidate the molecular mechanism behind sympathetic axon outgrowth inhibition. To understand signaling pathways a FRET based imaging platform will be used to examine multiple signaling pathways in parallel. These results will identify novel therapeutic targets to restore sympathetic axon outgrowth in the presence of CSPGs

项目摘要 心律失常引起的突发性心力衰竭是心脏病患者死亡的主要原因， 心肌梗死（MI）。心脏受损区域交感神经传递中的异源性 被认为是导致心律失常的原因MI后早期去神经支配后，受损的心脏 组织，或心脏疤痕，有能力刺激神经再支配，由于大量的分泌神经 激活原肌球蛋白受体激酶A（TrkA）的生长因子（NGF）。尽管如此，神经不会生长 由于硫酸软骨素蛋白聚糖（CSPG）的存在， 神经支配和去神经支配。由此产生的失神经组织无法对 交感神经传递导致产生心律失常的异质反应。 我们实验室以前的工作表明，阻断交感神经中的CSPG信号可以恢复交感神经系统的功能。 心脏瘢痕的神经支配，并降低MI后心律失常的易感性。治疗性干预， CSPG信号传导和恢复心脏瘢痕的交感神经支配将是一个可行的策略，以减少 心肌梗死后心律失常和心源性猝死的风险，但治疗设计受到我们对以下因素的理解的限制： CSPG信令。 CSPG是由糖胺聚糖修饰的不同核心蛋白组成的分子家族 (GAG)可以通过硫酸化进一步修饰的侧链。来自中枢神经系统研究的证据 中枢神经系统（CNS）的研究表明，轴突生长的抑制主要通过神经损伤后的4S-CSPG发生。 尽管CSPG在预防心脏瘢痕神经再支配中起着关键作用，但尚不清楚4S- CSPG特异性抑制交感神经轴突生长。这项研究将提供一个机械的理解 心脏瘢痕中的CSPG硫酸化如何影响我们的MI小鼠模型中的交感神经去神经支配， 选择性降解4S-CSPG的Arasulfatase B酶。此外，CSPG硫酸化诱导的信号传导 关注TrkA信号传导网络下游的研究将阐明TrkA信号传导网络下游的分子机制。 交感神经轴突生长抑制。为了了解信号通路，基于FRET的成像平台将 用于并行检查多个信号通路。这些结果将确定新的治疗靶点 在CSPG存在下恢复交感神经轴突生长