Innate Immunity to Spiral Ganglion Neuron Degeneration

对螺旋神经节神经元变性的先天免疫

• 批准号: 10640178
• 负责人: Tejbeer Kaur
• 金额: $ 4.17万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-08 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10640178
• 关键词: Acceleration; Afferent Neurons; Aging; Animals; Anti-Inflammatory Agents; Auditory; Binding; Biological; Blood; Brain; CSF1R gene; CX3CL1 gene; Candidate Disease Gene; Cell Death; Cells; Chemotaxis; Cochlea; Cochlear Implants; Cochlear implant procedure; DNA Sequence Alteration; Data; Development; Elements; Exposure to; Fractalkine; Future; Genetic Polymorphism; Goals; Hair Cells; Hearing; Heterogeneity; Human; Immune; Immunotherapy; Impairment; Individual; Inflammation; Inflammatory; Injury; Innate Immune System; Inner Hair Cells; Knockout Mice; Knowledge; Lead; Ligand Binding; Ligands; Macrophage; Maps; Measures; Mediating; Methods; Molecular; Mus; Mutant Strains Mice; Natural Immunity; Natural regeneration; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neuropathy; Nitrogen; Noise; Noise-Induced Hearing Loss; Outcome; Oxygen; Pathology; Pathway interactions; Performance; Pharmaceutical Preparations; Play; Population; Prevention; Production; Residual state; Risk; Role; Sensorineural Hearing Loss; Signal Transduction; Single Nucleotide Polymorphism; Structure; Synapses; Testing; Variant; chemokine; clinically relevant; cochlear synaptopathy; cytokine; deaf; density; hearing impairment; hearing loss risk; hearing restoration; humanized mouse; immune cell infiltrate; inhibitor; injured; monocyte; mouse model; neuron loss; neuronal survival; neuroprotection; neurotoxic; noise trauma; normal hearing; novel; novel therapeutics; ototoxicity; preservation; prevent; receptor; recruit; repaired; response; sound; spiral ganglion; success; therapy development; transmission process; treatment strategy

PROJECT SUMMARY Spiral ganglion neurons (SGNs), the primary afferent neurons in the cochlea, play vital functions in normal hearing by transmitting auditory information from the mechanosensory hair cells to the brain, and in restoration of hearing via cochlear implants in deaf individuals. However, exposure to traumatic and/or prolonged noise causes degeneration and subsequent loss of SGNs and their synaptic connections with hair cells in varied degrees, leading to degradation of auditory information, and impeding the performance of cochlear implants or future hair cell or synapse regeneration strategies. The reasons for such SGN degeneration remain unclear. To inform the development of novel therapies to preserve or regrow functional SGNs, it is critical to understand the biological mechanisms of SGN degeneration and survival in the injured cochlea. We have recently identified fractalkine signaling (CX3CL1-CX3CR1) between SGNs (which express chemokine CX3CL1 ligand) and innate- immune cells such as macrophages and monocytes (which express cognate CX3CR1 receptor) as a key neuroprotective signaling that promotes SGN survival and synapse repair in the injured cochlea. Here, we seek to examine the cellular and molecular mechanisms by which fractalkine signaling mediates neuroprotection in mouse cochleae following graded noise trauma. Specifically, Aim 1 will determine the precise roles of CX3CR1- expressing cochlear resident and blood-derived recruited macrophages in SGN survival or degeneration after noise trauma. Using fate mapping to distinguish and selectively deplete cochlear resident and recruited macrophages, we will test the hypothesis that CX3CR1-expressing recruited macrophages promote SGN survival after noise trauma. Aim 2 will determine whether CX3CR1 regulates macrophage responses after noise trauma such that absence of CX3CR1 results in an increased and sustained production of pro-inflammatory cytokines and reactive oxidative factors that is detrimental for SGN viability. Effector pro- and anti-inflammatory cytokines, and reactive oxygen and nitrogen species will be detected in both cochleae and macrophages with intact fractalkine signaling and those that lack CX3CR1 after noise trauma. Aim 3 will examine the relationship between human CX3CR1 polymorphisms and noise-induced hearing loss. Approximately 25-30% humans carry two single nucleotide polymorphisms (SNPs) in the CX3CR1 locus (hCX3CR1-I249/M280) that show defective binding to CX3CL1 ligand and loss of chemotactic function in macrophages. Using a novel humanized mouse model expressing the aforementioned human CX3CR1 SNPs, we will test the hypothesis that dysregulated macrophage responses due to impaired CX3CR1 signaling in these variants accelerates synapse and neuron loss and worsens hearing following noise trauma. Together, these studies will test fundamentally new hypotheses proposing specific elements of the innate immune system, macrophages and fractalkine signaling as critical targets for neuroprotective immunotherapies to promote synapse repair and SGN survival in an injured cochlea.

项目摘要 耳蜗中的主要传入神经元螺旋神经神经元（SGNS）在正常情况下起重要功能 通过将听觉信息从机械感应毛细胞传输到大脑，然后在恢复中听力 通过耳蜗植入物在聋人中听证。但是，暴露于创伤和/或长时间的噪声 导致SGN的变性和随后的损失及其与毛细胞的突触连接不同 学位，导致听觉信息退化，并阻碍人工耳蜗的性能或 未来的毛细胞或突触再生策略。这种SGN变性的原因尚不清楚。到 告知新型疗法的开发以保存或恢复功能SGN，了解 受伤的耳蜗中SGN变性和存活的生物学机制。我们最近确定了 SGN（表达趋化因子CX3CL1配体）和先天 - 免疫细胞，例如巨噬细胞和单核细胞（表达同源CX3CR1受体）作为钥匙 神经保护信号传导可促进受伤的耳蜗中SGN存活和突触修复。在这里，我们寻找 检查分子信号传导中介导神经保护的细胞和分子机制 小鼠耳蜗等级噪声创伤后。具体而言，AIM 1将确定CX3CR1-的精确作用 在SGN生存或变性中表达人工耳蜗居民和血液衍生的巨噬细胞 噪音创伤。使用命运映射区分和有选择地耗尽人工耳蜗并招募 巨噬细胞，我们将检验以下假设：表达CX3CR1的募集巨噬细胞可促进SGN存活 噪音创伤后。 AIM 2将确定CX3CR1在噪声创伤后是否调节巨噬细胞反应 因此，缺乏CX3CR1会导致促炎细胞因子的增加和持续产生 和反应性氧化因子对SGN生存力有害。效应子和抗炎细胞因子， 在Cochleae和巨噬细胞中都将检测到活性氧和氮种类 噪声创伤后缺乏CX3CR1的分裂信号传导。 AIM 3将检查 人CX3CR1多态性和噪声引起的听力损失。大约25-30％的人携带两个单一 CX3CR1基因座（HCX3CR1-I249/M280）中的核苷酸多态性（SNP）显示出与 CX3CL1配体和巨噬细胞中趋化功能的丧失。使用新型的人源化鼠标模型 表达上述人CX3CR1 SNP，我们将测试巨噬细胞失调的假设 这些变体中CX3CR1信号受损引起的响应会加速突触和神经元丧失，并且 噪音创伤后听到听到的情况恶化。这些研究将共同​​检验新的假设 提出先天免疫系统，巨噬细胞和分面信号的特定元素作为关键 神经保护免疫疗法的靶标，可促进受伤的耳蜗中突触修复和SGN存活。