Bilirubin Toxicity in the Auditory System

描述（由申请方提供）：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毒性的主要并发症。胆红素损伤的范围从典型的核黄疸伴听力损失和耳聋（部分由于新生儿较早出院，最近再次出现）到更细微的损伤，如听神经病、孤立性外周和中枢听觉功能障碍以及认知缺陷。胆红素中毒引起的听力损害的发生率很难与短暂性新生儿高胆红素血症有关。此外，尽管数十年的研究，发病机制，听觉功能障碍的网站，和脆弱性和可逆性的决定因素仍然只有部分了解。我们在胆红素脑病的经典古恩大鼠模型中使用了非侵入性电生理学与其他技术相结合，以了解关于听觉系统损伤定位的复杂和混乱的历史文献。我们已经证明了病理生理学的可逆性，并确定了毒性的潜在分子机制。我们建议扩展我们的生产性研究，使用非侵入性脑干听觉诱发电位（BAEPs），双耳BAEPs和一个新的未结合胆红素（UB）的血液测试在黄疸古恩大鼠。胆红素中毒后发生的BAEP和UB变化将与生化和解剖学指标进行比较。我们将评估旨在预防和逆转年轻大鼠胆红素毒性的假设驱动的干预措施，并调查老年动物的细微听觉后遗症。我们将胆红素诱导的听觉障碍的不同模式的胆红素暴露的量，持续时间和发展时间的差异，并定义可逆性的毒性动力学。在许多潜在的分子机制和标志物中，我们已经确定了钙/钙调蛋白依赖性激酶II和钙结合蛋白表达的变化，这些变化似乎与病理生理学和解剖学具有一致的关系。我们现在将使用这些标记物来研究胆红素毒性导致的选择性损伤和细胞死亡的发病机制。具体目标都是为了提供一个凝聚力和全面的表征的定位，易感性，可逆性，后遗症，由于胆红素毒性和其对正常发育过程和结果的影响听觉功能障碍的发病机制。拟议研究的结果应导致改进的非侵入性程序，用于预测，预防和治疗新生儿胆红素中毒的神经和听力并发症。

DESCRIPTION (provided by applicant): 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 damage ranges from classic kernicterus with hearing loss and deafness, which has recently reemerged due in part to the earlier discharge of newborns from hospitals, to more subtle damage, such as auditory neuropathy, isolated peripheral and central auditory dysfunction, and cognitive deficits. The incidence of auditory impairment due to bilirubin toxicity is difficult to relate to transient neonatal hyperbilirubinemia. In addition, the pathogenesis, sites of auditory dysfunction, and determinants of vulnerability and reversibility are still only partially understood despite decades of study. We have used non-invasive electrophysiology in combination with other techniques in the classic Gunn rat model of bilirubin encephalopathy to make sense of a complex and confusing historical literature regarding localization of damage in the auditory system. We have demonstrated reversibility of the pathophysiology, and have identified a potential molecular mechanism of the toxicity. We propose to extend our productive studies using noninvasive brainstem auditory evoked potentials (BAEPs), binaural BAEPs and a new unbound bilirubin (UB) blood test in the jaundiced Gunn rat. BAEP and UB changes that occur after bilirubin toxicity will be compared to biochemical and anatomical measures. We will evaluate hypothesis-driven interventions aimed at preventing and reversing bilirubin toxicity in young rats, and investigate subtle auditory sequelae in older animals. We will relate different patterns of biiirubin-induced auditory disorders to differences in the amount, duration, and the developmental timing of the bilirubin exposure, and define the kinetics of reversibility of the toxicity. Among many potential molecular mechanisms and markers, we have identified changes in expression of calcium/calmodulin-dependent kinase II and calcium binding proteins that seem to bear a consistent relationship with the pathophysiology and anatomy. We will now use these markers to investigate the pathogenesis of the selective damage and cell death due to bilirubin toxicity. The specific aims are all directed toward providing a cohesive and comprehensive characterization of the localization, susceptibility, reversibility, sequelae, and pathogenesis of auditory dysfunction due to bilirubin toxicity and its effect on normal developmental processes and outcomes. The findings of the proposed research should lead to improved noninvasive procedures for predicting, preventing, and treating the neurological and audiological complications of bilirubin toxicity in human newborns.