BILIRUBIN TOXICITY IN THE AUDITORY SYSTEM

脑损伤和听力障碍仍然是胆红素中毒的主要并发症，尽管新生儿高胆红素血症(黄疸)的治疗取得了进展。胆红素脑病的范围从核黄蜂最近在美国重新出现，部分原因是新生儿较早出院，到更轻微的损伤，如孤立的外周和中枢听觉功能障碍和认知障碍。胆红素毒性引起的细微或孤立损害的发生率尚不清楚，因为很难将新生儿发生的一过性异常与晚年出现的一过性异常联系起来。此外，尽管经过几十年的研究，但对听觉神经系统功能障碍的发病机制、部位以及易损性和可逆性的决定因素仍只有部分了解。因此，我们建议扩展我们的生产性研究，使用无创脑干听觉诱发电位(BAEP)，结合细胞内外电生理学、光镜和电子显微镜免疫组织化学以及定量生化研究，在有黄疸的Gunn大鼠胆红素脑病模型中。我们还将使用培养细胞模型和固定组织来确定胆红素毒性的基本机制。BAEP在暴露于胆红素毒性后不久发生的变化将与体内和体外的生化和免疫组织化学参数进行比较。我们还将评估旨在预防和逆转胆红素毒性的假设驱动的干预措施。这些研究的具体目的都是为了对胆红素毒性引起的功能障碍的定位、易感性和可逆性、发病机制及其对正常发育过程的影响提供全面的表征。这项拟议研究的结果应该有助于改进预测、预防和治疗新生儿胆红素中毒的神经学和听力学并发症的非侵入性程序。

Brain damage and auditory dysfunction continue to be major complications of bilirubin toxicity despite advances in the treatment of hyperbilirubinemia (jaundice) in newborns. The spectrum of bilirubin encephalopathy ranges from kernicterus, which has recently reemerged in this country due in part to the earlier discharge of newborns from hospitals to more subtle damage, such as isolated peripheral and central auditory dysfunction and cognitive deficits. The incidence of subtle of isolated impairment due to bilirubin toxicity is unknown because it is difficult to relate transient abnormalities that occur in the newborn with those that appear later in life. In addition the pathogenesis, sites of auditory nervous system dysfunction, and the determinants of vulnerability and reversibility are still only partially understood despite decades of study. Therefore, we propose to extend our productive studies using non-invasive brainstem auditory evoked potentials (BAEPs), in combination with intra- and extracellular electrophysiology, light and electron microscopic immunohistochemistry, and quantitative biochemical studies, in the jaundiced Gunn rat model of bilirubin encephalopathy. We will also use cultured cell models and fixed tissues to determine the fundamental mechanisms of bilirubin toxicity. BAEP changes that occur soon after exposure to bilirubin toxicity will be compared to biochemical and immunohistochemical parameters in vivo and in vitro. We will also evaluate hypothesis-driven interventions aimed at preventing and reversing bilirubin toxicity. The specific aims of the proposed studies are all directed toward providing a comprehensive characterization of the localization, susceptibility and reversibility, and pathogenesis of dysfunction due to bilirubin toxicity and its effect on normal developmental processes. The findings of the proposed research should lead to improved non-invasive procedures for predicting, preventing, and treating the neurological and audiological complications of bilirubin toxicity in human newborns.