BILIRUBIN TOXICITY IN THE AUDITORY SYSTEM

胆红素对听觉系统的毒性

• 批准号: 2125523
• 负责人: Steven Malcolm Shapiro
• 金额: $ 27.93万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-09-01 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2125523
• 关键词: NMDA receptors; auditory cortex; auditory nuclei; auditory pathways; auditory threshold; bilirubin; binaural hearing; calcium channel blockers; calcium flux; calcium indicator; calmodulin dependent protein kinase; cochlear microphonic potentials; congenital brain disorder; congenital deafness; ear hair cell; enzyme activity; hyperbilirubinemia; immunocytochemistry; laboratory rat; neural degeneration; neuroprotectants; neurotoxins; sulfonamides; tissue /cell culture

Human newborns are still at risk for brain damaged and hearing loss from bilirubin toxicity despite advances in the care and treatment of hyperbilirubinemia. The spectrum of bilirubin encephalopathy today ranges from classic kernicterus in premature, low-birth-weight infants, to more subtle conditions or the isolated sequelae of hearing loss and cognitive dysfunction. The incidence of impairment due to bilirubin toxicity, especially in the subtle or isolated conditions, is largely unknown because it is difficult to relate abnormalities that appear later in life to transient biochemical abnormalities that occur in the newborn period. Furthermore, the pathogenesis, localization of sites of auditory nervous system dysfunction, and the determinants of vulnerability and reversibility are still only partially understood despite decades of study. In a continuation of our successful use of brainstem auditory evoked potentials (BAEPs) in the Gunn rat model of bilirubin encephalopathy, we will combine noninvasive neurophysiological recordings with quantitative neuroanatomical studies, biochemical measurements, and immunohistochemistry to provide a cohesive synthesis of the localization, reversibility and pathogenesis of dysfunction due to bilirubin toxicity and its interaction with developmental processes. Electrophysiologic findings that occur soon after acute exposure to bilirubin toxicity will be compared to anatomic and biochemical measures. Interventions aimed at reversing acute bilirubin toxicity will be used to explore the time constraints of reversibility of the pathological process. Studies at different ages early in development will examine the vulnerability of different areas of the immature auditory and central nervous systems to bilirubin toxicity. We will continue our efforts to localize the specific site(s) of bilirubin-induced auditory nervous system dysfunction utilizing BAEPs, otoacoustic emissions, binaural interaction evoked potentials, and later-latency evoked potentials to assess damage to the cochlea and the central auditory nervous system, and verify our electrophysiologic results with anatomic and biochemical experiments. The resulting multidisciplinary approach is expected to provide new insights into the localization, pathogenesis, and reversibility of this disorder, and its effects on the auditory system. Understanding the complex relationships between electrophysiological, anatomical and biochemical processes in animal models of bilirubin encephalopathy should lead to improved noninvasive procedures for predicting, preventing, and treating the neurological and audiological sequelae of bilirubin toxicity in human newborns.

人类新生儿仍面临脑损伤和听力损失的风险 尽管胆红素毒性在护理和治疗方面取得了进步 高胆红素血症。当今胆红素脑病的范围包括 从早产儿、低出生体重儿的典型核黄疸，到更多 微妙的情况或听力损失和认知障碍的孤立后遗症 功能障碍。胆红素毒性导致的损伤发生率， 尤其是在微妙或孤立的条件下，很大程度上是未知的 因为很难将晚年出现的异常联系起来 新生儿期发生的短暂生化异常。 此外，听觉神经部位的发病机制、定位 系统功能障碍以及脆弱性的决定因素 尽管几十年来，可逆性仍然只被部分理解 学习。 延续我们成功使用脑干听觉诱发 胆红素脑病 Gunn 大鼠模型中的电位（BAEP），我们 将无创神经生理学记录与定量相结合 神经解剖学研究、生化测量以及 免疫组织化学提供定位的凝聚合成， 胆红素毒性导致的功能障碍的可逆性和发病机制 及其与发育过程的相互作用。 急性暴露后不久出现的电生理学结果 胆红素毒性将与解剖学和生化指标进行比较。 旨在逆转急性胆红素毒性的干预措施将用于 探索病理过程可逆性的时间限制。 在发育早期的不同年龄段进行的研究将考察 不成熟的听觉和中枢不同区域的脆弱性 神经系统对胆红素的毒性。我们将继续努力 定位胆红素诱导的听觉神经系统的特定部位 利用 BAEP、耳声发射、双耳交互的功能障碍 诱发电位和晚潜伏期诱发电位来评估损伤 耳蜗和中枢听觉神经系统，并验证我们的 解剖和生化实验的电生理结果。 由此产生的多学科方法预计将提供新的 深入了解这种现象的定位、发病机制和可逆性 障碍及其对听觉系统的影响。了解 电生理学、解剖学和 胆红素脑病动物模型中的生化过程应 导致改进的非侵入性程序用于预测、预防和 治疗胆红素中毒的神经和听力后遗症 在人类新生儿中。