Inner Ear Impact of Chronic Middle Ear Inflammation

慢性中耳炎症对内耳的影响

• 批准号: 7850348
• 负责人: DENNIS ROYAL TRUNE
• 金额: $ 44.16万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7850348
• 关键词: Acute; Adult; Anti-Inflammatory Agents; Anti-inflammatory; Bacteria; Bone Morphogenetic Proteins; C3H/HeJ Mouse; Cells; Child; Chronic; Clinical Treatment; Cochlea; Cochlear Diseases; Connective Tissue; Cytokine Gene; DNA; Development; Ear; Fibroblast Growth Factor; Gene Expression; Gene Expression Profile; Genes; Goals; Heating; Immune; Immune response; Inbred BALB C Mice; Inflammation; Inflammation Mediators; Inflammatory; Knockout Mice; Labyrinth; Lead; Mediating; Molecular Profiling; Mus; Otitis Media; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Peptides; Peptidoglycan; Phase; Process; Research; Role; Sensorineural Hearing Loss; Staging; Steroids; TLR2 gene; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Tissues; Toll-like receptors; Vascular Endothelial Growth Factors; cytokine; insight; killings; middle ear; middle ear disorder; mouse model; prevent; programs; public health relevance; therapy development; toll-like receptor 4

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.

描述（由申请人提供）：对导致内耳病理学的慢性中耳炎的炎症机制知之甚少。因此，该研究计划的长期目标是识别和防止慢性中耳疾病造成永久人工耳蜗的炎症过程。初步研究确定急性和慢性中耳炎症会诱导内耳组织的细胞因子基因表达。这种内耳的基因表达谱包括炎性介质以及组织重塑细胞因子，例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。这为媒体媒体的炎症机制提供了新的诱发机制的新见解。我们的初步研究还表明，如果足够早，类固醇治疗可以扭转这些耳蜗问题。因此，我们的基本假设是，如果适当的治疗治疗针对活性的特定炎症过程，则可以预防或反转慢性中耳炎中发生的感觉性听力损失和耳蜗组织重塑。拟议的研究将表征由于急性和慢性中耳炎症引起的内耳基因表达的病理机制，并评估如何通过靶向疗法控制这些病理过程。拟议的研究将利用接种热杀性细菌（急性中耳炎）和C3H/HEJ小鼠接种的BALB/C小鼠，这些小鼠缺陷TOLL样受体4（慢性耳鼻炎培养基）。 AIM 1将确定从急性到慢性中耳炎症进展过程中表达的内耳细胞因子基因； AIM 2将表征从急性到慢性中耳炎症进展过程中内耳组织重塑的基因； AIM 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细胞因子基因进行炎症和重塑，而AIM 4将开发出最合适的介入疗法，以控制从急性中雌性剧本到慢性中耳部炎症过程中内部耳朵基因表达的这些阶段。这些研究将确定由于中耳炎症引起的人工耳蜗病理学的特定基因表达机制，并开发可针对相关免疫过程的疗法。这将为患有慢性中耳炎的儿童和成人开发更好的临床治疗选择，以防止永久性的感觉性听力损失和其他耳蜗病理学。提出了一项研究来评估慢性中耳炎症导致人工耳蜗病理学的机制。急性和慢性中耳疾病的小鼠模型将评估不同细菌成分在中耳和内耳中细胞因子基因表达的作用，以及这种表达如何随着炎症转变从先天免疫反应到细胞介导的适应性免疫反应而变化。最后，各种治疗方法将针对这些特定的炎症阶段，以抑制免疫反应并保护内耳免受永久损害。