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: 8677869
• 负责人: David J. Lim
• 金额: $ 44.68万
• 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/8677869
• 关键词: Affect; Animal Experiments; Antibodies; Attenuated; Auditory; Bilateral; Caspase; Cell Death; Cells; Cisplatin; Clinical; Development; Down-Regulation; Generations; Goals; Immune; Inflammation Mediators; Inflammatory; Interferon Type II; Interferons; Interleukin-1; Labyrinth; Ligaments; MAPK8 gene; Mediating; Mediator of activation protein; Modeling; Molecular; NADPH Oxidase; NADPH Oxidase 1; NF-kappa B; Pathogenesis; Phase; RIPK1 gene; Reactive Oxygen Species; Regulation; Role; STAT1 gene; Sensorineural Hearing Loss; Sensory; Signal Pathway; Signal Transduction; Superoxides; Surface; TNF gene; Therapeutic; Tissues; Tumor Necrosis Factor-alpha; Up-Regulation; base; cytokine; cytotoxic; cytotoxicity; intercellular communication; novel strategies; ototoxicity; response; therapeutic target

DESCRIPTION (provided by applicant): 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-( (TNF-(). 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-( is required for cisplatin-induced ototoxicity and that down-regulation of TNF-( attenuates cisplatin-induced auditory damage. These results led us to focus on TNF-(-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-( in animal experiments, indicating the requirement of sensitization for TNF-(-mediated inner ear cytotoxicity. Therefore, we aim to determine the molecular mechanism involved in: (1) SLF's TNF-( induction in response to IL-1, a model inflammatory mediator; and (2) sensitization of the auditory sensory cells to induce TNF-(-mediated cytotoxicity via interferon-( (IFN-(). In addition, we plan to determine the therapeutic potential of targeting the key molecules involved in IFN-(-sensitized TNF-(-mediated cytotoxicity, which will provide us with a scientific basis for the development of a novel strategy to manage IMSNHL.

描述（由申请人提供）：由于进行性双侧受累和潜在的可逆性，免疫介导的感音神经性听力损失（IMSNHL）具有临床重要性。目前，由于对IMSNHL的分子发病机制了解甚少，因此尚无针对IMSNHL的特异性治疗靶点。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 的发病机制很大程度上未知，但无论起始因素如何，IMSNHL 的最终病程通常与免疫介导的耳蜗细胞（感觉和非感觉）损伤有关。免疫介导的组织损伤通常涉及通过表面分子的直接细胞间信号传导，例如抗体依赖性细胞毒性；以及通过肿瘤坏死因子-(TNF-()等细胞因子的间接信号传导。之前，我们已经证明螺旋韧带纤维细胞（SLF）响应炎症信号而释放介质，并且SLF衍生分子直接吸引炎症细胞。因此，我们假设SLF通过响应炎症介质和 释放化学吸引力和细胞毒性分子。我们还发现 TNF-( 的分泌是顺铂诱导的耳毒性所必需的，并且 TNF-( 的下调可减轻顺铂诱导的听觉损伤。这些结果使我们将重点放在 TNF-( 介导的细胞毒性作为免疫介导的内耳损伤的机制。然而，听觉感觉细胞 在动物实验中，似乎只有极高浓度的 TNF-( 才会受到损害，这表明 TNF-( 介导的内耳细胞毒性需要敏化。因此，我们的目的是确定参与以下分子机制：(1) SLF 响应 IL-1（一种模型炎症介质）而诱导 TNF-( ；(2) 听觉感觉细胞敏化以诱导 TNF-(-通过干扰素-(IFN-()介导的细胞毒性。此外，我们计划确定针对 IFN-(-致敏 TNF-(-介导的细胞毒性的关键分子) 的治疗潜力，这将为我们开发治疗 IMSNHL 的新策略提供科学依据。