Inner Ear Impact of Chronic Middle Ear Inflammation

描述(申请人提供)：对慢性中耳炎导致内耳病理的炎症机制知之甚少。因此，这项研究计划的长期目标是识别和预防慢性中耳疾病导致永久性耳蜗损伤的炎症过程。初步研究表明，急、慢性中耳炎症可通过内耳组织诱导细胞因子基因表达。这种内耳基因表达谱包括炎症介质以及组织重塑细胞因子，如成纤维细胞生长因子(FGF)、骨形态发生蛋白(BMP)、血管内皮生长因子(VEGF)等。这为研究中耳炎导致永久性耳蜗炎的机制提供了新的见解，如感觉神经性听力损失。我们的初步研究还表明，如果及早发现，类固醇治疗可以扭转这些耳蜗病。因此，我们的基本假设是，如果针对活跃的特定炎症过程进行适当的治疗，可以预防或逆转慢性中耳炎发生的感觉神经性听力损失和耳蜗组织重塑。这项拟议的研究将描述急性和慢性中耳炎引起的内耳基因表达的病理机制，并评估如何通过靶向治疗来控制这些病理过程。拟议的研究将利用接种了热致死细菌(急性中耳炎)的BALB/c小鼠和Toll样受体4(慢性中耳炎)缺陷的C3H/HeJ小鼠。目标1将确定从急性中耳炎到慢性中耳炎进展过程中内耳细胞因子基因的表达；目标2将表征从急性中耳炎到慢性中耳炎进展过程中内耳组织重塑的相关基因；目标3将利用不同的Toll样受体基因敲除小鼠来确定哪些细菌成分和炎症途径调节特定的耳蜗炎症和重塑细胞因子基因；以及目标4将开发最合适的介入疗法来控制从急性中耳炎到慢性中耳炎过程中内耳基因表达的这些阶段。这些研究将确定由于中耳炎症而导致的耳蜗病理的特定基因表达机制，并开发针对相关免疫过程的治疗方法。这将为为患有慢性中耳炎的儿童和成人开发更好的临床治疗方案奠定重要基础，以防止永久性感音神经性听力损失和其他耳蜗病。一项研究建议评估慢性中耳炎导致耳蜗病理学的机制。急性和慢性中耳疾病的小鼠模型将评估不同细菌成分对中耳和内耳细胞因子基因表达的影响，以及随着炎症从先天免疫反应过渡到细胞介导的适应性免疫反应，这种表达如何变化。最后，针对炎症的这些特定阶段进行各种治疗，以抑制免疫反应，保护内耳免受永久性损害。

DESCRIPTION (provided by applicant): Little is known of the inflammatory mechanisms of chronic otitis media that lead to inner ear pathology. Therefore, the long-term goal of this research program is to identify and prevent the inflammatory processes by which chronic middle ear disease causes permanent cochlear damage. Preliminary studies have determined that acute and chronic middle ear inflammation induces cytokine gene expression by inner ear tissues. This inner ear gene expression profile includes inflammatory mediators, as well as tissue remodeling cytokines, such as fibroblast growth factors (FGF), bone morphogenetic proteins (BMP), vascular endothelial growth factor (VEGF), etc. This has provided new insights into the inflammatory mechanisms by which otitis media causes permanent cochlear changes, such as sensorineural hearing loss. Our preliminary studies also showed that steroid treatments can reverse these cochlear problems if caught early enough. Therefore, our underlying hypothesis is that the sensorineural hearing loss and cochlear tissue remodeling that occurs in chronic otitis media can be prevented or reversed if the proper therapeutic treatment is targeted to the specific inflammatory process that is active. The proposed study will characterize the pathologic mechanisms of inner ear gene expression due to acute and chronic middle ear inflammation and assess how these pathologic processes can be controlled by targeted therapies. The proposed studies will utilize BALB/c mice inoculated with heat-killed bacteria (acute otitis media) and C3H/HeJ mice defective for Toll-like receptor 4 (chronic otitis media). Aim 1 will determine the inner ear cytokine genes expressed during the progression from acute to chronic middle ear inflammation; Aim 2 will characterize the genes underlying inner ear tissue remodeling during the progression from acute to chronic middle ear inflammation; Aim 3 will exploit different toll-like receptor knockout mice to determine which bacterial components and inflammatory pathways regulate specific cochlear cytokine genes for inflammation and remodeling, and Aim 4 will develop the most appropriate interventional therapies to control these phases of inner ear gene expression during the progression from acute to chronic middle ear inflammation. These studies will identify the specific gene expression mechanisms underlying cochlear pathology due to middle ear inflammation and develop therapies that can be targeted to the relevant immune processes. This will lay important groundwork for the development of better clinical treatment options for children and adults with chronic otitis media to prevent permanent sensorineural hearing loss and other cochlear pathology. A study is proposed to evaluate the mechanisms by which chronic middle ear inflammation leads to cochlear pathology. Mouse models for acute and chronic middle ear disease will assess the role of different bacterial components on cytokine gene expression in the middle and inner ear and how this expression changes as inflammation transitions from an innate immune response to a cell-mediated adaptive immune response. Finally, various treatments will be targeted to these specific phases of inflammation to suppress the immune responses and protect the inner ear from permanent damage.