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）：免疫介导的感官听力损失（IMSNHL）由于进行性双边参与和潜在可逆性而具有临床重要性。当前，由于其分子发病机理的了解很少，因此无法获得特定于IMSNHL的治疗靶标。我们的长期目标是阐明免疫介导的内耳损伤的分子机制，从而导致SNHL。 IMSNHL的疗法发生在很大程度上是未知的，但是无论起始因素如何，IMSNHL的最终过程通常与耳蜗细胞的免疫介导的损伤有关（感觉和非感觉）。免疫介导的组织损伤通常涉及通过表面分子（例如抗体依赖性细胞毒性）进行直接细胞 - 细胞信号传导。和通过细胞因子（例如肿瘤坏死因子）的间接信号传导 - （（（tnf-（）。先前。我们已经证明，螺旋韧带纤维细胞（SLFS）响应响应信号而释放介体因炎症信号和SLF衍生分子而直接受到炎症的影响，因此，我们假设受到炎症的影响。释放趋化性和细胞毒性分子。似乎仅受到极高浓度的TNF-的损害（在动物实验中，表明对TNF的敏化需要 - （ - 介导的内耳细胞毒性。因此，我们旨在确定：（1）SLF的TNF-（对IL-1的响应IL-1，模型的促进剂，诱导SLF的TNF- （2）听觉感觉细胞诱导TNF的敏化 - （ - 通过干扰素 - （（（IFN-（）。此外，我们计划确定靶向靶向IFN中涉及的关键分子的治疗潜力 - （ - （ - 介导的细胞毒性基础）可以与我们一起进行科学的策略，以实现我们的开发，并为我们提供了一项科学的策略。