BILIRUBIN TOXICITY IN THE AUDITORY SYSTEM

尽管新生儿高胆红素血症（黄疸）的治疗取得了进展，但脑损伤和听觉功能障碍仍然是胆红素中毒的主要并发症。胆红素脑病的范围从核黄疸到更细微的损害，如孤立的外周和中枢听觉功能障碍和认知缺陷，核黄疸最近在美国重新出现，部分原因是新生儿较早出院。由于胆红素毒性引起的轻微或孤立损害的发生率尚不清楚，因为很难将新生儿中发生的一过性异常与以后出现的异常联系起来。此外，尽管经过数十年的研究，听觉神经系统功能障碍的发病机制、部位以及脆弱性和可逆性的决定因素仍然只有部分了解。因此，我们建议在黄疸的古恩大鼠模型中使用非侵入性脑干听觉诱发电位（BAEP），结合细胞内和细胞外电生理学、光镜和电镜免疫组织化学以及定量生化研究来扩展我们的富有成效的研究。胆红素脑病。我们还将使用培养的细胞模型和固定的组织来确定胆红素毒性的基本机制。将暴露于胆红素毒性后不久发生的BAEP变化与体内和体外的生化和免疫组化参数进行比较。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。拟议研究的具体目的均旨在提供胆红素毒性所致功能障碍的定位、易感性和可逆性以及发病机制及其对正常发育过程的影响的全面表征。拟议研究的结果应导致改进的非侵入性程序，用于预测，预防和治疗人类新生儿胆红素毒性的神经和听力并发症。

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.