Role of Spiral Ligament Fibrocytes in Inner Ear Inflammation

螺旋韧带纤维细胞在内耳炎症中的作用

• 批准号: 7459496
• 负责人: Sung K. Moon
• 金额: $ 18.6万
• 依托单位: HOUSE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459496
• 关键词: Academic achievement; Acoustic Trauma; Affect; Animal Model; Binding; Binding Sites; Biological Models; CCL2 gene; Cells; Child Language; Chronic; Cochlea; Complication; Cytomegalovirus; Development; Effector Cell; Enhancers; Epithelial Cells; Etiology; Frequencies; Future; Goals; Gram-Negative Bacteria; Hair Cells; Hearing; Hearing Tests; Immune; In Vitro; Incidence; Inflammation; Inflammatory; Labyrinth; Language Development; Ligaments; Light; Mediating; Mediator of activation protein; Meniere' s Disease; Modeling; Molecular; Mus; Nontypable Haemophilus influenza; Otitis Media; Pathogenesis; Patients; Phosphorylation; Phosphorylation Site; Play; Recruitment Activity; Role; Secondary to; Sensorineural Hearing Loss; Signal Pathway; Testing; Toll-Like Receptor 2; Transcriptional Activation; Up-Regulation; cell injury; cell type; chemokine; ear infection; hearing impairment; in vivo Model; inner ear diseases; middle ear; monocyte; mouse toll-like receptor 2; novel therapeutics; pathogen; prevent

DESCRIPTION (provided by applicant): Inflammation is associated with many inner ear disorders of unknown etiology. It is believed that otitis media (OM)-associated inner ear inflammation results in high frequency sensorineural hearing loss (SNHL) in as high as 3% of OM patients. Moreover, the incidence can be underestimated because ultrahigh-frequency SNHL and transient hearing threshold shifts are hard to detect with routine hearing tests. However, it is not well known which type of inner ear cells involved in inner ear inflammation by recognizing bacterial molecules and recruiting inflammatory cells. The spiral ligament fibrocytes (SLFs) produce inflammatory mediators such as MCP1, attracting monocytes. Monocytes predominantly infiltrate cochlea with chronic OM or acoustic trauma. This makes MCP1 the ideal SLF-derived chemokine, attracting effector cells and causing inner ear damage. Nontypeable Haemophilus influenzae (NTHI) is the model organism for inducing inner ear inflammation, which is one of the major OM pathogens. Interestingly, toll-like receptor 2 (TLR2) plays a significant role in recognizing NTHI molecules in the epithelial cells even though it is a Gram-negative bacterium. We hypothesize that SLFs recognize NTHI molecules and release MCP1 through TLR2-dependent NF?B activation. Furthermore, we hypothesize that NTHI-induced MCP1 up-regulation is involved in inner ear inflammation secondary to OM, resulting in SNHL. We therefore propose the following three Specific Aims to test our hypotheses:; 1. Do SLFs release MCP1 upon recognition of NTHI through the TLR2-dependent signaling pathway? We will determine TLR2 expression in the cochlea and involvement of the TLR2-MyD88 signaling pathway in recognizing NTHI molecules by SLFs in both in vitro and in vivo models. 2. Does NTHI-induced MCP1 up-regulation require NF?B activation mediated by I?K¿-dependent I?Ba phosphorylation? We will investigate the involvement of I?K¿-dependent I?Ba phosphorylation in NTHI-induced MCP1 up- regulation and identify the specific NF?B subunits and binding sites that are responsive to NTHI. 3. Does the blockage of NTHI-induced MCP1 up-regulation prevent inner ear inflammation secondary to OM We will determine if the presence of NTHI lysate and MCP1 in the middle ear cavity cause inner ear inflammation, resulting in SNHL and explore the possibility of blocking TLR2 and depleting MCP1 to inhibit NTHI-induced SNHL. We believe that this project can shed light on the molecular pathogenesis of inner ear complications secondary to OM. Furthermore, the findings will facilitate future development of novel therapeutic strategies to prevent potential inner ear complications of OM. The goal of this project is to study how middle ear infection affects the inner ear. We aim to investigate the molecular pathogenesis related to bacterial recognition in the inner ear, inner ear inflammation, inner ear damage and hearing loss.

描述（由申请人提供）：炎症与许多病因不明的内耳疾病有关。据信，与中耳炎 (OM) 相关的内耳炎症会导致高达 3% 的 OM 患者出现高频感音神经性听力损失 (SNHL)。此外，由于超高频 SNHL 和瞬时听力阈值变化很难通过常规听力测试检测到，因此发生率可能被低估。然而，目前尚不清楚哪种类型的内耳细胞通过识别细菌分子和招募炎症细胞来参与内耳炎症。螺旋韧带纤维细胞 (SLF) 产生 MCP1 等炎症介质，吸引单核细胞。慢性 OM 或声损伤时单核细胞主要浸润耳蜗。这使得 MCP1 成为理想的 SLF 衍生趋化因子，吸引效应细胞并造成内耳损伤。不可分型流感嗜血杆菌（NTHI）是诱发内耳炎症的模式生物，是 OM 的主要病原体之一。有趣的是，Toll 样受体 2 (TLR2) 在识别上皮细胞中的 NTHI 分子方面发挥着重要作用，尽管它是革兰氏阴性细菌。我们假设 SLF 识别 NTHI 分子并通过 TLR2 依赖性 NF?B 激活释放 MCP1。此外，我们假设 NTHI 诱导的 MCP1 上调与 OM 继发的内耳炎症有关，从而导致 SNHL。因此，我们提出以下三个具体目标来检验我们的假设：； 1. SLFs通过TLR2依赖性信号通路识别NTHI后是否释放MCP1？我们将在体外和体内模型中确定耳蜗中的 TLR2 表达以及 TLR2-MyD88 信号通路在 SLF 识别 NTHI 分子中的参与情况。 2. NTHI诱导的MCP1上调是否需要由I?K¿依赖性I?Ba磷酸化介导的NF?B激活？我们将研究 I?K? 依赖性 I?Ba 磷酸化在 NTHI 诱导的 MCP1 上调中的作用，并鉴定对 NTHI 敏感的特定 NF?B 亚基和结合位点。 3.阻断NTHI诱导的MCP1上调是否可以预防OM继发的内耳炎症我们将确定中耳腔中NTHI裂解物和MCP1的存在是否会引起内耳炎症，从而导致SNHL，并探讨阻断TLR2和消耗MCP1以抑制NTHI诱导的SNHL的可能性。 我们相信该项目可以揭示继发于 OM 的内耳并发症的分子发病机制。此外，这些发现将有助于未来开发新的治疗策略，以预防 OM 潜在的内耳并发症。 该项目的目标是研究中耳感染如何影响内耳。我们的目的是研究与内耳细菌识别、内耳炎症、内耳损伤和听力损失相关的分子发病机制。