权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Innate Immunity to Spiral Ganglion Neuron Degeneration

对螺旋神经节神经元变性的先天免疫

基本信息

批准号：
10880051
负责人：
Tejbeer Kaur
金额：
$ 48.83万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-08 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10880051
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

项目摘要

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.

项目摘要螺旋神经节神经元（SGN）是耳蜗的初级传入神经元，在正常耳蜗发育过程中发挥着重要作用。听觉通过将听觉信息从机械感觉毛细胞传递到大脑，通过人工耳蜗植入来恢复听力。然而，暴露于创伤性和/或长时间的噪音导致SGN及其与毛细胞突触连接的变性和随后的损失，程度，导致听觉信息的退化，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。到为保护或再生功能性SGN的新疗法的开发提供信息，了解 SGN变性和受损耳蜗存活的生物学机制。我们最近发现 SGN（表达趋化因子CX 3CL 1配体）和先天性巨噬细胞之间的Fractalkine信号传导（CX 3CL 1-CX 3CR 1）免疫细胞如巨噬细胞和单核细胞（其表达同源CX 3CR 1受体）作为关键神经保护信号，促进受损耳蜗中SGN存活和突触修复。在这里，我们寻求研究fractalkine信号转导介导神经保护的细胞和分子机制，分级噪声损伤后小鼠耳蜗。具体来说，目标1将确定CX 3CR 1的确切作用，在SGN存活或变性中表达耳蜗驻留和血液来源的募集巨噬细胞，噪音创伤利用命运映射区分和选择性地去除耳蜗驻留和招募巨噬细胞，我们将检验表达CX 3CR 1的募集巨噬细胞促进SGN存活的假设在噪音创伤后。目的2将确定CX 3CR 1是否调节噪声损伤后的巨噬细胞反应使得CX 3CR 1的缺乏导致促炎细胞因子的增加和持续产生和对SGN活力有害的反应性氧化因子。促炎和抗炎细胞因子效应物，在耳蜗和巨噬细胞中检测到活性氧和氮， fractalkine信号和那些缺乏CX 3CR 1噪音创伤后。目标3将研究以下两者之间的关系人类CX 3CR 1多态性与噪声性听力损失大约25-30%的人携带两个单一的 CX 3CR 1基因座（hCX 3CR 1-I249/M280）中的核苷酸多态性（SNP）显示与 CX 3CL 1配体与巨噬细胞趋化功能丧失使用一种新的人源化小鼠模型表达上述人CX 3CR 1 SNPs，我们将检验调节失调的巨噬细胞由于这些变体中受损的CX 3CR 1信号传导引起的反应加速了突触和神经元损失，噪声损伤后听力受损。总之，这些研究将从根本上检验新的假设，提出先天免疫系统的特定元素，巨噬细胞和fractalkine信号传导是关键的神经保护性免疫疗法的靶点，以促进受损耳蜗中的突触修复和SGN存活。