Otitis Media Impact on the Inner Ear

描述（由申请人提供）：尽管进行了数十年的研究，但仍然不清楚中耳炎如何影响内耳导致感音神经性听力损失。因此，不可能预测谁处于危险之中，或者可以使用什么标志物来确定是否发生内耳炎症，这使得有效的诊断和管理变得困难。因此，我们的bng长期目标是确定中耳炎症是如何导致耳蜗病变的。PI及其同事最近开发了急性中耳炎小鼠模型，并描述了C3 H/HeJ小鼠中的慢性中耳炎，其Toll样受体4（TLR 4）存在缺陷。这些合作导致了新方法的开发，以表征中耳和内耳细胞因子表达，核因子-kB（NF-kB）介导的炎症过程，一氧化氮介导的耳蜗损伤和定量免疫细胞病理学。本研究将利用这些急性和慢性中耳疾病小鼠模型来建立相关的中耳和内耳免疫谱。这将首次描述中耳炎可直接引起内耳病理的分子免疫机制。因此，这项研究有可能显着提高我们对急性和慢性中耳炎引起的内耳炎症过程的理解，并为开发检测和治疗感音神经性听力损失的新方法奠定基础。拟定的研究将利用在中耳中接种热灭活的嗜血性流感病毒或肺炎链球菌的BALB/c小鼠（急性中耳炎）和TLR 4缺陷的C3 H/HeJ小鼠（慢性中耳炎）来表征内耳病理学、生理学、细胞因子基因表达、细胞因子水平、NF-κ B激活的炎症过程和活性氧。本提案的具体目标是：目标1：描述急性中耳炎的内耳炎症特征。这将检验急性中耳炎引起以Thl炎症过程为特征的短暂内耳免疫应答的假设。目的2：探讨慢性中耳炎内耳炎症的特点。这将检验慢性中耳炎引起以扩展的Th 1炎症过程为特征的持续性和破坏性内耳免疫应答的假设。将通过听性脑干反应测听、耳蜗内电位、光学和电子显微镜以及炎症介质的免疫组织化学来测量内耳病理学。将通过测量炎性细胞因子、细胞因子基因表达以及转录因子、血管相关因子和活性氧的ELISA来评估补体免疫介导的过程。

DESCRIPTION (provided by applicant): In spite of decades of study, it is still not clear how otitis media impacts the inner ear to cause sensorineural hearing loss. Thus, it is impossible to predict who is at risk or what markers can be used to determine if inner ear inflammation is occurring, making effective diagnosis and management difficult. Therefore, our bng-term goal is to identify how inflammation in the middle ear causes cochlear pathology. The PI and his colleagues, has recently developed an acute otitis media mouse model, as well as described chronic otitis media in the C3H/HeJ mouse that has a defect in its toll like receptor 4 (TLR4). These collaborations have led to the development of new methods to characterize both middle ear and inner ear cytokine expression, nuclear factor-kB (NF-kB)-mediated inflammatory processes, nitric oxide-mediated cochlear damage, and quantitative immune cell pathology. The proposed studies will capitalize on both these acute and chronic middle ear disease mouse models to establish the correlative middle ear and inner ear immune profiles. This will describe for the first time the molecular immune mechanisms by which otitis media can directly cause inner ear pathology. Therefore, this research has the potential to significantly advance our understanding of inner ear inflammatory processes elicited by both acute and chronic otitis media and lay the groundwork for development of new procedures for the detection and therapy of sensorineural hearing loss. The proposed studies will utilize BALB/c mice inoculated in the middle ear with heat-killed Haemophilous influenza or Streptococcus pneumoniae (acute otitis media) and C3H/HeJ mice defective for TLR4 (chronic otitis media) to characterize inner ear pathology, physiology, cytokine gene expression, cytokine levels, NF- kB activated inflammatory processes, and reactive oxygen species. The specific aims of this proposal are: Aim 1: To characterize the inner ear inflammatory profile in acute otitis media. This will test the hypothesis that acute otitis media causes a transient inner ear immune response characterized by Thl inflammatory processes. Aim 2: To characterize the inner ear inflammatory profile in chronic otitis media. This will test the hypothesis that chronic otitis media causes a persistent and destructive inner ear immune response characterized by expanded Th1 inflammatory processes. Inner ear pathology will be measured with auditory brainstem response audiometry, the endocochlear potential, light and electron microscopy, and immunohistochemistry of inflammatory mediators. Cochlear immune-mediated processes will be assessed by measurement of inflammatory cytokines, cytokine gene expression, and ELISA of transcription factors, vascular related factors, and reactive oxygen species.