Bilirubin Toxicity in the Auditory System

描述(申请人提供)：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。胆红素损伤的范围从典型的核黄体症伴听力损失和耳聋，最近重新出现，部分原因是新生儿较早出院，到更轻微的损伤，如听神经病，孤立的外周和中枢听觉功能障碍，以及认知障碍。胆红素毒性所致听力损害的发生率很难与一过性新生儿高胆红素血症有关。此外，尽管经过几十年的研究，但对听觉功能障碍的发病机制、位置以及易损性和可逆性的决定因素仍只有部分了解。在经典的Gunn大鼠胆红素脑病模型中，我们结合使用了无创电生理学和其他技术，以理解关于听觉系统损伤定位的复杂而令人困惑的历史文献。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，使用无创脑干听觉诱发电位(BAEP)，双耳BAEP和一种新的无结合胆红素(UB)血液测试在黄斑性Gunn大鼠。胆红素中毒后BAEP和UB的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幼年大鼠胆红素毒性的假说驱动的干预措施，并调查老年动物的细微听觉后遗症。我们将把胆红素引起的听力障碍的不同模式与胆红素暴露的量、持续时间和发育时间的不同联系起来，并定义毒性可逆性的动力学。在许多潜在的分子机制和标志物中，我们已经确定了钙/钙调蛋白依赖蛋白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引起的选择性损伤和细胞死亡的发病机制。这些特定的目标都是为了提供一个连贯和全面的特征，描述由胆红素毒性引起的听觉功能障碍的定位、易感性、可逆性、后遗症和发病机制，以及它对正常发育过程和结果的影响。这项拟议的研究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。

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.