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

• 批准号: 9380214
• 负责人: STEVEN H GREEN
• 金额: $ 63.34万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-05 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9380214
• 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; Hearing; Hearing Impaired Persons; Histologic; Immune; Immune Cell Activation; 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 Cells; Nature; Nerve Degeneration; Neuroimmune; Neurons; Pathology; Performance; Pharmaceutical Preparations; Phenotype; Play; Process; Rattus; Receptor Cell; Recruitment Activity; 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; deafness; experimental study; ganglion cell; immune activation; immunological status; in vivo; injured; loss of function; macrophage; neuron loss; neuronal survival; neuroprotection; neurotoxic; neurotoxicity; neurotrophic factor; novel strategies; ototoxicity; postnatal; prevent; response; restoration; spiral ganglion

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听觉信息从耳蜗毛细胞传递到耳蜗神经元 原子核因此，螺旋神经节和耳蜗核神经元对于正常听力和听觉发育是必不可少的。 通过耳蜗或耳蜗核植入物恢复聋人的听力。但在一些 在某些情况下，这些神经元可能在耳聋后退化或死亡，限制了这些神经元的潜在功效。 装置.这种神经变性的原因及其在毛细胞死亡后的可变性质仍不清楚。 我们实验室最近的发现表明，先天免疫系统的元素被招募到 提示免疫细胞的激活状态是 这是两种结构中神经元存活的重要决定因素。我们还表明，这些元素的 先天免疫系统对听觉神经元的存活有着深远的影响，在某些情况下， 细胞毒性，在其他情况下可能具有神经保护作用。在至少一种耳聋模型中，免疫反应， 值得注意的是，这可能是致聋后螺旋神经节神经元死亡的主要原因。解决这些 先天免疫系统对听觉神经元存活的复杂和不同的影响-长期 我们的目标是开发神经保护的免疫疗法-我们建议系统地删除特定的 天然免疫系统的组成部分，包括自然杀伤（NK）细胞，巨噬细胞或小胶质细胞， 确定它们对神经元存活的影响。实验将使用转基因小鼠，在某些情况下， 抑制性抗体巨噬细胞和NK细胞都被招募到螺旋神经节中以响应毛发 细胞损伤拟议的实验将确定巨噬细胞和NK细胞是否具有神经毒性， 神经保护在损伤的耳蜗和特定的细胞因子和趋化因子在刺激和 这些免疫细胞的潜在神经毒性一个平行的系列研究将集中在神经免疫 耳蜗核中的相互作用，其中一个co-PI的广泛研究表明， 存活取决于在出生后早期成熟的“关键时期”的传入输入。相比之下，成熟 耳蜗核神经元在去传入后存活。初步数据显示，这可能是由于 小胶质细胞（CNS的常驻免疫细胞）的神经保护作用。拟议中的实验将验证这一点 假说.总之，这些研究将从根本上测试新的假设，这些假设涉及到 先天免疫系统作为神经保护性治疗的关键（如果不是最佳的话）靶点， 耳蜗和听性脑干神经元。