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：
7903517
负责人：
Sung K. Moon
金额：
$ 8.53万
依托单位：
HOUSE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-03 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7903517
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

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

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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（适用提供）：炎症与许多未知病因的内耳疾病有关。据认为，中耳炎（OM）相关的内耳感染会导致高频感官听力损失（SNHL）高达3％的OM患者。此外，由于超高频率SNHL和瞬时听力阈值转移很难通过常规听力测试检测到这一事件。但是，尚不清楚通过识别细菌分子和募集炎症细胞而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，吸引单核细胞。单核细胞主要用慢性OM或声学创伤浸润。这使MCP1成为理想的SLF衍生趋化因子，吸引效应细胞并导致内耳损伤。不可用的嗜血杆菌影响（NTHI）是诱导内耳感染的模型生物，这是主要的OM病原体之一。有趣的是，即使是革兰氏阴性细菌，Toll样受体2（TLR2）在识别上皮细胞中的NTHI分子方面起着重要作用。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上调与继发于OM的内耳感染有关，从而导致SNHL。因此，我们提出以下三个特定目标来检验我们的假设：； 1。SLF是否在通过TLR2依赖性信号通路识别NTHI后会释放MCP1？我们将确定TLR2在耳蜗中的TLR2表达和TLR2-MYD88信号通路的参与，以识别SLF在体外和体内模型中SLF的NTHI分子。 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NTHI诱导的MCP1上调中I？k¿依赖性i？ba磷酸化的参与，并确定对NTHI响应的特定NF？B亚基和结合位点。 3。nthi诱导的MCP1上调的阻塞是否阻止了继发于OM的内耳感染，我们将确定中耳腔中NTHI裂解物和MCP1是否是否引起内耳感染，导致SNHL，并探索阻断TLR2和DEPLETING MCP1的可能性，以抑制Nththi-thi-thi-thi-thi-thi-thi-thi-thi-thi-thi-thi-thi-thi-thi-thi-thi-thi-thi-thi-thi-thi-thi-thi-thi-thi-thi-Snhl snhl。我们认为，该项目可以阐明其继发于OM的内耳并发症的分子发病机理。此外，这些发现将促进未来的新型热策略发展，以防止OM潜在的内耳并发症。该项目的目的是研究中耳感染如何影响内耳。我们的目的是研究与内耳感染，内耳感染，内耳损伤和听力丧失相关的分子发病机理。