Role of Spiral Ligament Fibrocytes in Immune-Mediated Inner Ear Damage

螺旋韧带纤维细胞在免疫介导的内耳损伤中的作用

• 批准号: 8795862
• 负责人: David J. Lim
• 金额: $ 39.86万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8795862
• 关键词: Role; Spiral; Ligament; Fibrocytes; Immune

Project Summary/Abstract Immune-mediated sensorineural hearing loss (IMSNHL) is of clinical importance because of progressive bilateral involvement and potential reversibility. Currently, the therapeutic targets specific to IMSNHL are not available because its molecular pathogenesis is poorly understood. Our long-term goal is to elucidate the molecular mechanism of immune-mediated inner ear damage, resulting in SNHL. Etiopathogenesis of IMSNHL is largely unknown, but regardless of the initiating factors, the final course of IMSNHL is commonly associated with immune-mediated damage of the cochlear cells (sensory and non- sensory). Immune-mediated tissue damage generally involves direct cell-cell signaling via surface molecules such as antibody-dependent cytotoxicity; and indirect signaling via cytokines such as tumor necrosis factor-a (TNF-a). Previously, we have demonstrated that spiral ligament fibrocytes (SLFs) release mediators in response to inflammatory signals and SLF-derived molecules directly attract the inflammatory cells. Therefore, we hypothesize that SLFs are key players in immune-mediated inner ear damage by responding to inflammatory mediators and releasing chemoattractive and cytotoxic molecules. We also found that secretion of TNF-a is required for cisplatin-induced ototoxicity and that down-regulation of TNF-a attenuates cisplatin-induced auditory damage. These results led us to focus on TNF-a-mediated cytotoxicity as a mechanism of immune- mediated inner ear damage. However, the auditory sensory cells appeared to be damaged only by the extremely high concentration of TNF-a in animal experiments, indicating the requirement of sensitization for TNF-a-mediated inner ear cytotoxicity. Therefore, we aim to determine the molecular mechanism involved in: (1) SLF's TNF-a induction in response to IL-1, a model inflammatory mediator; and (2) sensitization of the auditory sensory cells to induce TNF-a-mediated cytotoxicity via interferon-g (IFN-g). In addition, we plan to determine the therapeutic potential of targeting the key molecules involved in IFN-g-sensitized TNF-a-mediated cytotoxicity, which will provide us with a scientific basis for the development of a novel strategy to manage IMSNHL.

项目概要/摘要 免疫介导的感音神经性听力损失 (IMSNHL) 具有重要的临床意义，因为 渐进的双边参与和潜在的可逆性。目前，治疗靶点具体为 IMSNHL 尚不可用，因为其分子发病机制尚不清楚。我们的长期目标是 阐明免疫介导的内耳损伤导致 SNHL 的分子机制。 IMSNHL 的发病机制在很大程度上尚不清楚，但无论起始因素如何，最终病程 IMSNHL 的发生通常与免疫介导的耳蜗细胞（感觉细胞和非细胞细胞）损伤有关。 感官）。免疫介导的组织损伤通常涉及通过表面分子的直接细胞信号传导 例如抗体依赖性细胞毒性；以及通过肿瘤坏死因子-a 等细胞因子的间接信号传导 (TNF-a)。 之前，我们已经证明螺旋韧带纤维细胞（SLF）会释放介质以响应 炎症信号和 SLF 衍生分子直接吸引炎症细胞。因此，我们 假设 SLF 通过响应炎症而在免疫介导的内耳损伤中发挥关键作用 介质并释放化学吸引力和细胞毒性分子。我们还发现TNF-a的分泌 顺铂诱导的耳毒性所需，并且 TNF-a 的下调可减弱顺铂诱导的耳毒性 听觉损伤。这些结果使我们关注 TNF-a 介导的细胞毒性作为免疫机制 介导的内耳损伤。 然而，听觉感觉细胞似乎只有在极高浓度的情况下才会受到损害。 动物实验中TNF-a的变化，表明TNF-a介导的内耳需要致敏 细胞毒性。因此，我们的目的是确定以下分子机制：（1）SLF诱导TNF-a 响应 IL-1（一种模型炎症介质）； (2) 听觉感觉细胞的敏化以诱导 TNF-a 通过干扰素-g (IFN-g) 介导的细胞毒性。此外，我们计划确定治疗潜力 靶向参与 IFN-g 致敏 TNF-a 介导的细胞毒性的关键分子，这将为我们提供 为制定管理 IMSNHL 的新战略提供了科学依据。