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Role of the Innate Immune System in the Survival of Auditory Neurons

先天免疫系统在听觉神经元存活中的作用

基本信息

批准号：
10183216
负责人：
STEVEN H GREEN
金额：
$ 59.15万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-05 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183216
关键词：
Ablation Acoustic Trauma Acoustics Address Aging Aminoglycosides Antibodies Auditory Auditory system Behavior Blocking Antibodies Brain Brain Stem CX3CL1 gene Cell Death Cells Cessation of life Cochlea Cochlear Implants Cochlear nucleus Coculture Techniques Complex Data Deafferentation procedure Devices Ear Elements Excision Fractalkine Gene Expression Gene Expression Profiling Goals Hair Cells Histologic Immune Immune response Immune system Immunosuppressive Agents Immunotherapy Implant Individual Injury Innate Immune System Interleukin-18 Knock-in Mouse Knock-out Labyrinth Mediating Methods Microglia Modeling Mouse Strains Mus NK Cell Activation Natural Killer Cell toxicity Natural Killer Cells Nature Nerve Degeneration Neuroimmune Neurons Pathology Performance Phenotype Play Process Rattus Receptor Cell Research Role Schwann Cells Series Signal Transduction Spinal Ganglia Spleen Structure System Testing Transgenic Mice base cell injury cell killing cell type chemokine critical period cytokine cytotoxic cytotoxicity deaf deafening deafness experimental study ganglion cell hearing restoration immune activation immunological status in vivo injured loss of function macrophage neuron loss neuronal survival neuroprotection neurotoxic neurotoxicity neurotrophic factor normal hearing novel strategies ototoxicity postnatal prevent recruit response spiral ganglion

项目摘要

Spiral ganglion neurons transmit auditory information from cochlear hair cells to the neurons of the cochlear nucleus. Thus, spiral ganglion and cochlear nucleus neurons are essential for normal hearing and for restoration of hearing via cochlear or cochlear nucleus implants in deaf individuals. However, in some circumstances these neurons may degenerate or die after deafening, limiting the potential efficacy of these devices. The reasons for this neurodegeneration and its variable nature after hair cell death remain unclear. Recent findings from our labs have revealed that elements of the innate immune system are recruited to the spiral ganglion and cochlear nucleus after deafening and suggest that the activation status of immune cells is an important determinant of neuronal survival in both structures. We also show that these elements of the innate immune system have profound effects on the survival of the auditory neurons, in some cases being cytotoxic, in others possibly neuroprotective. In at least one deafness model, the immune response, remarkably, may be a principal cause of spiral ganglion neuronal death after deafening. To resolve these complex and disparate effects of the innate immune system on auditory neuronal survival – with the long-term goal of developing immunotherapies for neuroprotection – we propose to systematically delete specific components of the innate immune system involving Natural Killer (NK) cells, macrophages, or microglia to determine their effect on neuronal survival. The experiments will use transgenic mice and, in some cases, inhibitory antibodies. Both macrophages and NK cells are recruited into the spiral ganglion in response to hair cell injury. The proposed experiments will determine whether macrophages and NK cells are neurotoxic or neuroprotective in the injured cochlea and the roles of specific cytokines and chemokines in stimulation and potential neurotoxicity of these immune cells. A parallel series of studies will focus on neuroimmune interactions in the cochlear nucleus, in which extensive research by one of the co-PI's has shown that neuronal survival depends on afferent input during a `critical period' in early postnatal maturation. In contrast, mature cochlear nucleus neurons survive deafferentation. Preliminary data suggest that this may be due to neuroprotection by microglia (the resident immune cells of the CNS.) The proposed experiments will test this hypothesis. Together, these studies will test fundamentally new hypotheses implicating specific components of the innate immune system as critical, if not optimal, targets for neuroprotective therapies to promote survival of cochlea and auditory brainstem neurons after cochlear pathology.

螺旋神经节神经元将耳蜗毛细胞的听觉信息传递给耳蜗神经元