ROLE OF THE INNATE IMMUNE SYSTEM IN THE SURVIVAL OF AUDITORY NEURONS

先天免疫系统在听觉神经元生存中的作用

• 批准号: 10119786
• 负责人: Edwin W Rubel
• 金额: $ 40.43万
• 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/10119786
• 关键词: Ablation; Acoustics; Administrative Supplement; Affect; Afferent Neurons; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein Precursor; Apoptosis; Auditory; Auditory system; Behavior; Biological; Biological Models; Brain; Brain Stem; CX3CL1 gene; Cell Death; Cell Nucleus; Cells; Clinical Research; Cochlea; Cochlear Implants; Cochlear nucleus; Cognitive; Data; Deafferentation procedure; Dementia; Development; Ear; Equilibrium; Event; Excision; Fractalkine; Gene Expression; Gene Mutation; Gene Proteins; Genes; Goals; Grant; Hair Cells; Human; Inflammation; Inflammatory; Injury; Innate Immune System; Interleukin-18; Knock-in; Labyrinth; Link; MAPT gene; Mediating; Microglia; Motor; Mus; Mutate; Mutation; Natural Killer Cells; Nerve Degeneration; Neurons; Organ; Outcome; Outcome Study; Parents; Pathology; Performance; Peripheral; Presbycusis; Presenile Alzheimer Dementia; Protein Fragment; Proteins; Risk; Rodent; Role; Senile Plaques; Sensory; Sensory Ganglia; Sensory Hair; Signal Transduction; Synapses; System; Testing; Transgenic Organisms; Vestibular ganglion; abeta deposition; age related; amyloid formation; auditory pathway; base; deprivation; experimental study; hearing impairment; inner ear development; macrophage; mouse model; neonatal brain; normal hearing; relating to nervous system; response; sensory input; spiral ganglion; tau Proteins

Numerous clinical studies have suggested a link between loss of sensory function in the inner ear and the development of Alzheimer’s disease, but the biological basis of this association is not clear. The neurodegeneration that occurs in Alzheimer’s disease (AD) is thought to be caused by aberrant processing and clustering of protein fragments derived from amyloid precursor protein (APP) and the microtubule-associated protein Tau. Certain identified mutations in APP and Tau are also known to greatly increase the risk of developing AD. The study of AD-related degeneration in mouse models presents certain challenges. Because of small differences in the sequences of AD-associated genes in humans vs. rodents, mice do not normally develop AD- like neurodegeneration. However, a number of transgenic knock-in lines that express human forms of these AD- associated gene mutations have been created, facilitating the study of amyloid- and Tau-mediated pathology. We are requesting an administrative supplement to our R01 grant, “Role of the Innate Immune System in the Survival of Auditory Neurons”, in order to test for cellular degeneration in the inner ears and auditory brainstem nuclei of a widely-used mouse model of Alzheimer’s disease. Our pilot data show that both APP and Tau are highly expressed by hair cells and afferent neurons of the inner ear, raising the possibility that mutated forms of these proteins might promote age-related loss of hearing and balance function. It is further possible that the loss of sensory function in such mice makes neurons of the CNS more susceptible to AD pathology and degeneration. One set of proposed experiments will examine whether there is increased loss of spiral ganglion and vestibular ganglion neurons in AD-model mice, and whether the sensory ganglia of these mice contain amyloid plaques and increased numbers of inflammatory cells. Prior studies from our labs have also shown that once the auditory system has matured, the survival of the neurons in the cochlear nucleus is not dependent on maintained sensory input. We hypothesize that expression of AD-associated genes will make these neurons become vulnerable to the loss of synaptic input from the ear, such as routinely occurs with aging. A second set of experiments will test this hypothesis by determining if the expression of AD-associated mutations causes the neurons of the ventral cochlear nucleus (VCN) to show increased vulnerability to loss of sensory input. Such an event might result in a cascade of peripheral and central events leading to increased cognitive and sensory motor decline. The outcome of these studies may help explain the link between hearing loss and the devilment of Alzheimer’s pathology.

许多临床研究表明，内耳感觉功能丧失与 阿尔茨海默病的发展，但这种关联的生物学基础尚不清楚。的 阿尔茨海默病（AD）中发生的神经变性被认为是由异常处理引起的， 来自淀粉样前体蛋白（APP）和微管相关的蛋白片段的聚类 Tau蛋白。APP和Tau中的某些鉴定的突变也已知会大大增加发展成糖尿病的风险。 AD.在小鼠模型中研究AD相关变性存在一定的挑战。因为小 人类与啮齿类动物AD相关基因序列的差异，小鼠通常不会发生AD， 比如神经退化然而，许多表达人类形式的这些AD的转基因敲入系， 相关的基因突变已经产生，促进了淀粉样蛋白和Tau介导的病理学的研究。 我们正在请求对我们的R01补助金进行行政补充，“先天免疫系统在免疫系统中的作用”。 听觉神经元的存活”，以测试内耳和听觉脑干中的细胞变性 广泛使用的阿尔茨海默病小鼠模型的细胞核。我们的试点数据显示，APP和Tau都是 内耳的毛细胞和传入神经元高度表达，提高了突变形式的 这些蛋白质可能促进与年龄相关的听力和平衡功能的丧失。更有可能的是， 在这种小鼠中感觉功能的降低使得CNS的神经元更易受AD病理和变性的影响。 一组拟议的实验将检查是否有螺旋神经节和前庭神经节的损失增加， AD模型小鼠的神经节神经元，以及这些小鼠的感觉神经节是否含有淀粉样蛋白斑块 以及炎症细胞数量的增加。我们实验室之前的研究也表明，一旦听觉 系统已经成熟，耳蜗核中神经元的存活不依赖于维持的感觉神经元。 输入.我们假设AD相关基因的表达会使这些神经元变得容易受到 来自耳朵的突触输入的丧失，例如随着年龄的增长而经常发生的。第二组实验将测试 通过确定AD相关突变的表达是否会导致腹侧神经元 耳蜗核（VCN）显示增加的脆弱性损失的感觉输入。这样的事件可能会导致 导致认知和感觉运动下降增加的外周和中枢事件级联。成果 这些研究可能有助于解释听力损失和阿尔茨海默病病理发展之间的联系。