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

基本信息

批准号：
7575698
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
项目类别：
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/7575698
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 Inflammation Mediators Inflammatory Labyrinth Language Development Ligaments Light Mediating Meniere&apos 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 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

项目摘要

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) 相关的内耳炎症导致高达 3% 的高频感音神经性听力损失 (SNHL)。此外，由于常规听力测试很难检测到超高频 SNHL 和瞬时听力阈值变化，因此 OM 患者的发病率可能被低估。然而，尚不清楚内耳涉及哪种类型的内耳细胞。螺旋韧带纤维细胞 (SLF) 会产生炎症介质，例如 MCP1，从而吸引单核细胞。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。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型生物，内耳炎症是主要的 OM 之一。提示，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，但我们努力让 SLF 识别 NTHI 分子并通过 TLR2 依赖性 NF 释放 MCP1。此外，我们发现 NTHI 诱导的 MCP1 上调与 OM 继发的内耳炎症有关，因此我们提出以下三个具体目标。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SLFs识别NTHI分子中的参与。 2. NTHI诱导的MCP1上调是否需要I?K介导的NF?B激活？依赖I?Ba 磷酸化？我们将研究I?K¿ 的参与情况。 NTHI 诱导的 MCP1 上调中依赖的 IκBa 磷酸化，并鉴定对 NTHI 敏感的特定 NFκB 亚基和结合位点。 3. 阻断 NTHI 诱导的 MCP1 上调是否可以预防内耳继发 OM 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，导致 SNHL 并探讨阻断 TLR2 的可能性并消耗 MCP1 以抑制 NTHI 诱导的 SNHL。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预防 OM 潜在内耳并发症的新治疗策略。该项目的目标是研究中耳感染如何影响内耳，我们的目标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。