DISEASE MECHANISMS IN ASNHL AND ITS MOUSE MODEL

ASNHL及其小鼠模型的疾病机制

• 批准号: 7035082
• 负责人: VINCENT K TUOHY
• 金额: $ 32.83万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-05 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035082
• 关键词: RNase protection assay; T cell receptor; auditory threshold; autoimmune disorder; clinical research; cytotoxic T lymphocyte; disease /disorder etiology; disease /disorder model; enzyme linked immunosorbent assay; epitope mapping; extracellular matrix proteins; hearing tests; helper T lymphocyte; histocompatibility antigens; human subject; immune response; immune tolerance /unresponsiveness; interferon gamma; interleukin 5; laboratory mouse; labyrinth; leukocyte activation /transformation; peptide chemical synthesis; phenotype; proteins; recombinant proteins; sensorineural hearing loss; tissue /cell culture

DESCRIPTION (provided by applicant): Autoimmune sensorineural hearing loss (ASNHL) is the most common cause of sudden hearing loss in adults and is typically characterized by a bilateral, rapidly progressive hearing deficit that responds therapeutically to corticosteroid treatment. Despite its name, data implicating autoimmunity in the etiopathogenesis of ASNHL have been limited, and targeted self-antigens have not been identified. We have recently shown that ASNHL patients have increased frequencies of inner ear-specific interferon-gamma- producing T cells in their peripheral blood compared to age- and sex-matched control subjects. Thus, inner ear-specific proinflammatory T cells appear to be implicated in the etiopathogenesis of ASNHL. Moreover, we have found that a targeted T cell response to defined inner ear specific peptides is capable of mediating hearing loss in SWXJ mice. In the current application, our working hypothesis is that ASNHL is at least in part a T cell-mediated organ-specific autoimmune disorder of the inner ear. Our proposed experiments are designed to identify and characterize the hierarchy of inner ear-specific target antigens and T cell repertoires involved in the development, progression, and immunoregulation of both human ASNHL and its murine counterpart. The significance of ASNHL as opposed to other forms of hearing loss resides in its potential for medical intervention. We believe that our proposed experimental design will substantially advance our understanding of ASNHL and thereby provide a basis for developing contemporary immunomodulatory therapies that may dramatically change and improve treatment of this debilitating hearing disorder.

描述（由申请人提供）：自身免疫性感音神经性听力损失（ASNHL）是成人突发性听力损失的最常见原因，其典型特征是双侧、快速进展的听力缺陷，对皮质类固醇治疗有治疗反应。尽管有其名称，但表明 ASNHL 发病机制中自身免疫的数据有限，并且尚未确定有针对性的自身抗原。我们最近发现，与年龄和性别匹配的对照受试者相比，ASNHL 患者外周血中产生内耳特异性干扰素 γ 的 T 细胞的频率增加。因此，内耳特异性促炎 T 细胞似乎与 ASNHL 的发病机制有关。此外，我们发现，针对特定内耳特异性肽的靶向 T 细胞反应能够介导 SWXJ 小鼠的听力损失。在当前的应用中，我们的工作假设是 ASNHL 至少部分是 T 细胞介导的内耳器官特异性自身免疫性疾病。我们提出的实验旨在识别和表征参与人类 ASNHL 及其小鼠对应物的发育、进展和免疫调节的内耳特异性靶抗原和 T 细胞库的层次结构。与其他形式的听力损失相比，ASNHL 的重要性在于其医疗干预的潜力。我们相信，我们提出的实验设计将大大增进我们对 ASNHL 的理解，从而为开发当代免疫调节疗法奠定基础，这些疗法可能会极大地改变和改善这种使人衰弱的听力障碍的治疗。