Development of Effective Strategies for Tinnitus Diagnosis and Treatment

制定有效的耳鸣诊断和治疗策略

• 批准号: 8990875
• 负责人: Avril Genene Holt
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-11-01 至 2017-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8990875
• 关键词: Acoustic Trauma; Acoustics; Affect; Animal Model; Animals; Attenuated; Auditory; Auditory Brainstem Responses; Biological Markers; Budgets; Calcium Channel; Calcium Channel Blockers; Data; Development; Diagnosis; Disease; Dorsal; Drug Evaluation; Drug Targeting; Electrophysiology (science); Evaluation; Exhibits; Exposure to; Fire - disasters; Future; Generations; Genes; Goals; Health; Hearing; Helicopter; Human; Image; Individual; Inferior Colliculus; Intervention; Lead; Magnetic Resonance Imaging; Manganese; Measures; Methods; Military Personnel; Modeling; Monitor; Neurons; Noise; Pathology; Patients; Perception; Pharmaceutical Preparations; Population; Prevention; Rattus; Reflex action; Reporting; Research; Services; Signal Transduction; Source; Sprague-Dawley Rats; Stimulus; Temporary Threshold Shift; Testing; Therapeutic Intervention; Tinnitus; Training; United States; Veterans; War; arm; attenuation; base; combat; diagnosis evaluation; diagnostic biomarker; differential expression; disability; drug efficacy; efficacy testing; experience; hearing impairment; high risk; novel; prevent; research study; restoration; sound; specific biomarkers; voltage; weapons

DESCRIPTION (provided by applicant): Tinnitus, the perception of ringing or buzzing in the absence of an acoustic stimulus, is a significant problem in the United States and is of specific concern for the military personnel. For the second consecutive year tinnitus is again the number one compensated disability with more than $1.2 billion paid in disability benefits in 2010. From training to deployment and combat activity, the military population is constantly exposed to acoustic trauma from weapons fire, tracked and non-tracked vehicles, airplanes and helicopters as well as bombs and grenades. Since tinnitus often results from exposure to loud noise, military personnel are at high risk of developing tinnitus. There is currently no cure for tinnitus. In order to develop appropriate pharmacological interventions, metrics that can be used as indicators of tinnitus attenuation are critically needed. Several studies report increased neuronal activity in the inferior colliculus (I) as a result of tinnitus. This suggests that monitoring neuronal activity in IC neurons may provide a useful biomarker for the diagnosis of tinnitus. A novel non-invasive method for assessment of neuronal activity is manganese enhanced MRI (MEMRI). Our group and others have used MEMRI to evaluate neuronal activity in auditory neurons (Yu et al., 2007; Brozoski et al. 2007; Holt et al., 2010). Although tinnitus sufferers often report loud, sustained or impulse noise exposure as a trigger for their tinnitus, many people with tinnitus do not sustain a permanent hearing loss. Thus, the biomarker for tinnitus needs to be apparent regardless of hearing status or method of tinnitus generation. Our proposed studies use several models of tinnitus (PTS-permanent threshold shift tone; TTS-temporary threshold shift tone; and SAFTS-small arms fire threshold shift noise) and build on our previous report suggesting that increased neuronal activity in the IC identified by MEMRI may be a reliable diagnostic marker for tinnitus. Having the capability of definitively associating a specific biomarker with the perception of tinnitus allows for testing the efficacy of pharmacological intervention. We have recently shown that tinnitus results in differential expression of voltage gated calcium channel (CaV) genes. Furthermore, our preliminary studies have shown that pharmacological administration of CaV blockers prior to the generation of tinnitus greatly reduced the perception of tinnitus. Therefore we will use two metrics, tinnitus perception and increased spontaneous neuronal activity in the IC, as indicators of tinnitus and assessment of these two metrics will be used as a method for evaluation of drugs proposed for pharmacological interventions. The research proposed in this application offers a path both to objective diagnosis of tinnitus and therapeutic interventions.

描述（由申请人提供）： 耳鸣是在没有声学刺激的情况下对响起或嗡嗡作响的感知，在美国是一个重要的问题，对军事人员特别关注。为了 连续第二年的耳鸣再次是2010年的第一批补偿残疾，在2010年支付了超过12亿美元的残疾福利。由于耳鸣通常是由于暴露于大声噪音的原因而导致的，因此军事人员有发病的高风险。目前无法治愈耳鸣。为了制定适当的药理干预措施，至关重要的是可以用作耳鸣衰减指标的指标。几项研究报告说，由于耳鸣，下丘（I）的神经元活性增加。这表明监测IC神经元中的神经元活性可能为诊断耳鸣提供有用的生物标志物。一种用于评估神经元活性的新型非侵入性方法是锰增强的MRI（MEMRI）。我们的小组和其他人使用MEMRI评估了听觉神经元中的神经元活性（Yu等，2007； Brozoski等，2007； Holt等，2010）。尽管耳鸣患者经常报告大声，持续或冲动的噪音暴露是耳鸣的触发，但许多耳鸣的人并不能承受永久性的听力损失。因此，无论听力状态或发作的方法如何，耳鸣的生物标志物都需要显而易见。我们提出的研究使用了几种耳鸣模型（PTS-永久性阈值移位音； TTS - 临时阈值移位音调；和Safts-Small Arms Fire fir fir threshold ships噪声），并建立在我们先前的报告上，这表明MEMRI在IC中的神经元活动增加可能是可靠的诊断诊断标记物的可靠诊断标记。具有将特定生物标志物与耳鸣的感知相关联的能力，可以测试药理干预的功效。我们最近表明，耳鸣会导致电压门控钙通道（CAV）基因的差异表达。此外，我们的初步研究表明，在产生耳鸣之前对CAV阻滞剂进行药理学给药可大大降低耳鸣的感知。因此，我们将使用两个指标，耳鸣感知和IC中自发性神经元活性的增加，作为耳鸣的指标，对这两个指标的评估将用作评估药物干预措施的药物的方法。该应用中提出的研究既可以客观地诊断耳鸣和治疗性干预措施。