Contribution of Macrophages and Fractalkine Towards Degeneration and Repair of Cochlear Synapses

巨噬细胞和分形蛋白对耳蜗突触退化和修复的贡献

• 批准号: 10090991
• 负责人: Tejbeer Kaur
• 金额: $ 25.55万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-05 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10090991
• 关键词: Acoustic Nerve; Animals; Attenuated; Auditory; Axon; Binding; Brain; CX3CR1 gene; Cells; Cessation of life; Cochlea; Cochlear Implants; Data; Development; Diagnosis; Environment; FDA approved; Fractalkine; Functional disorder; Future; Genetic; Glutamates; Goals; Hair Cells; Hearing; Hearing Tests; Hearing problem; Immune; Immunotherapy; Impairment; Individual; Injury; Innate Immune System; Inner Hair Cells; Intervention; Lead; Measures; Membrane; Microglia; Molecular; Mus; Natural regeneration; Nerve Degeneration; Nerve Fibers; Neurites; Neurons; Neuropathy; Noise; Noise-Induced Hearing Loss; Outcome; Pathology; Peptides; Performance; Peripheral; Pharmaceutical Preparations; Prevention; Protein Isoforms; Research Design; Role; Sensory Hair; Signal Transduction; Synapses; Testing; Therapeutic; Trauma; afferent nerve; axonal degeneration; base; cochlear synaptopathy; cytokine; density; drug preservation; efficacy testing; excitotoxicity; experience; hair cell regeneration; hearing impairment; hearing preservation; hearing restoration; hidden hearing loss; improved; in vivo; insight; interest; macrophage; neuron loss; neurotrophic factor; noise trauma; novel; overexpression; preservation; prevent; receptor; recruit; regenerative therapy; relating to nervous system; repaired; ribbon synapse; speech recognition; spiral ganglion

PROJECT SUMMARY/ABSTRACT Noise trauma can primarily damage the synaptic connections between the inner hair cells and the peripheral axons of the spiral ganglion neurons. Noise-induced synaptopathy is attributed to glutamate excitotoxicity and leads to gradual axonal degeneration and ultimately death of the spiral ganglion neurons. The consequences of loss of synapses and neurons include auditory perceptual dysfunctions leading to difficulty in speech recognition and listening in noisy environments. This type of auditory dysfunction is known as “hidden hearing loss” because it is not readily diagnosed through standard hearing tests. Moreover, absence of spiral ganglion neurons limits the performance of primary therapies for hearing loss such as cochlear implants and future hair cell regeneration strategies. Currently, there are no approved drugs that promote neuron survival or elicit regeneration of lost auditory nerves and replenish their synaptic connections with surviving hair cells. Therefore, it is of great interest to understand the mechanisms for synaptic and neuron degeneration and regeneration for the development of better ototherapeutics. We recently demonstrated that synaptopathic noise trauma is sufficient to recruit macrophages (innate-immune cells) towards the damaged inner hair cell-synaptic region. While the damaged synapses can undergo spontaneous repair however, disruption of fractalkine signaling (by genetic deletion of fractalkine (FKN) receptor CX3CR1 on macrophages) impairs such spontaneous synaptic repair and increases spiral ganglion neuron loss after trauma. These data imply that intact fractalkine signaling is necessary for synaptic repair and neuron survival in the damaged cochlea. Here, we propose to investigate the effect of activation of fractalkine signaling on prevention and repair of loss of synapses and neuron survival following cochlear trauma. Aim 1 will determine whether FKN treatment repairs damaged synapses after noise trauma or excitotoxic insult in mammalian mouse cochlea. Specifically, FKN peptide will be injected either (transtympanically) after synaptopathic noise trauma in vivo or after glutamate- induced excitotoxicity in cochlear explants. The precise contribution of FKN membrane or soluble isoforms towards synaptic repair will be examined. Aim 2 will determine whether FKN treatment reduces degeneration of synapses following noise trauma or glutamate excitotoxicity. We will treat with FKN membrane or soluble isoforms prior to glutamate treatment in ex vivo cochlear explants or prior to noise trauma in vivo (transtympanically). In Aim 3, we will eliminate cochlear macrophages and examine the influence of this intervention on the degree of synaptic degeneration and repair after synaptopathic noise trauma. For each aim, auditory function along with morphometric analyses of hair cell, macrophage, synapse and spiral ganglion neuron counts will be performed. Together, the study design will aid in investigating the effect of macrophages and fractalkine treatment on cochlear synapse degeneration and repair and hearing restoration and may lead to identification of novel fractalkine-based therapeutics for “hidden-hearing loss”.

项目摘要/摘要 噪声创伤主要可能损害损害损害损害损害损害损害损害损害伤害伤害伤害伤害伤害伤害伤害伤害 螺旋神经神经元的轴突。 导致轴突变性，最终导致螺旋神经元的死亡 突触丧失和神经元inurons包括听觉感知功能障碍对语音的差异 在嘈杂的环境中识别和聆听。 损失”，因为它尚未准备好通过标准听力测试诊断的诊断。此外，缺乏螺旋 神经节神经元限制了用于听力损失的主要疗法的性能，例如耳蜗植入物和植入物IND 未来的毛细胞再生策略目前没有促进神经元生存的批准药物 或引起失去的听觉神经的再生，并将其突触连接补充与存活的毛细胞。 因此，了解突触和神经元变性的机制以及 再生以发展更好的其他无形噪声 创伤足以将巨噬细胞（先天性免疫细胞）募集到受损的内毛细胞突触 区域。 信号传导（通过遗传缺失（FKN）受体CX3CR1在巨噬细胞上的遗传缺失）会损害这种情况 创伤后，自发的突触修复并增加了螺旋神经神经元的损失。 完整的分裂信号传导对于受损的耳蜗中的突触修复和神经元存活是必需的。 我们建议研究分子信号传导激活对预防和修复损失的影响 耳蜗创伤后的突触和神经元存活。 修复噪声创伤或哺乳动物小鼠耳蜗中的突触损坏。 具体而言，在体内突触噪声创伤之后，将（三翼型）注入FKN肽 或谷氨酸诱导的兴奋性人口毒剂的精确贡献。 可溶性同工型将检查突触修复。 减少噪声创伤或谷氨酸兴奋剂后突触的变性。 在离体耳蜗外植体中或噪声创伤之前进行谷氨酸治疗之前的膜或可溶同工型 体内（在AIM 3中）。 突触噪声创伤后的突触变性和修复装置的访谈 每个目标，听觉功能以及毛细胞，巨噬细胞，突触和螺旋的形态分析 神经节计数将共同执行。 巨噬细胞和分子治疗对耳蜗突触变性和修复和听力恢复的治疗 并可能导致鉴定出新型的基于分裂的治疗方法，以实现“隐藏听力损失”。