BILIRUBIN TOXICITY IN THE AUDITORY SYSTEM

人类新生儿仍有脑损伤和听力损失的风险 胆红素毒性尽管在护理和治疗方面取得了进展 高胆红素血症。目前胆红素脑病的范围很广。 从早产儿、低出生体重婴儿的经典核心黄蜂到更多 细微情况或听力损失和认知障碍的孤立后遗症 功能障碍。胆红素中毒所致损害的发生率， 特别是在微妙或孤立的条件下，基本上是未知的 因为很难将生命后期出现的异常现象联系起来 发生在新生儿期的一过性生化异常。 此外，对听神经的发病机制、部位定位进行了探讨。 系统功能障碍，以及脆弱性和 尽管几十年来人们对可逆性仍只有部分了解 学习。 在我们成功使用脑干听觉诱发的基础上 Gunn大鼠胆红素脑病模型的BAEP 将无创神经生理记录与量化相结合 神经解剖研究，生化测量，以及 免疫组织化学提供了一个内聚合成的定位， 胆红素毒性功能障碍的可逆性及发病机制 以及它与发育过程的相互作用。 急性接触后不久出现的电生理学表现 胆红素毒性将与解剖和生化指标进行比较。 旨在逆转急性胆红素中毒的干预措施将用于 探讨病理过程可逆性的时间限制。 在发育早期的不同年龄的研究将检验 未成熟听觉和中枢不同区域的易损性 神经系统对胆红素的毒性。我们将继续努力 胆红素诱发听觉神经系统的特定部位定位(S) 脑干听觉诱发电位功能障碍、耳声发射、双耳交互作用 诱发电位和后潜伏期诱发电位评估损伤 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学结果。 由此产生的多学科方法预计将提供新的 对该病的定位、发病机制和可逆性的见解 紊乱，以及它对听觉系统的影响。了解 电生理学、解剖学和生物力学之间的复杂关系 胆红素脑病动物模型的生化过程 导致改进非侵入性程序以预测、预防和 胆红素中毒的神经系统和听力学后遗症的治疗 在人类新生儿中，GRANT=R03DC02094 这项拟议中的研究的目标是了解分子 控制神经发生的机制。许多病理学都涉及到 神经系统退化，包括阿尔茨海默氏症、亨廷顿氏症 和帕金森氏症。同样，脊髓损伤可能会导致 由于神经通路的损伤而导致的瘫痪。大多数神经元 在脊椎动物中是终末分化的，在 损坏。了解参与神经元发育的过程和 分化可能最终会产生治疗这些神经元的方法。 涉及修复或替换受损神经元的病理学。 研究哺乳动物的嗅觉系统几乎是无与伦比的。 脊椎动物的神经发生。嗅觉感觉神经元再生 在整个生命过程中都来自干细胞。此过程涉及扩展 树突通向粘膜表面，轴突通向嗅球。这个 来自嗅觉上皮单个区域的神经元表达不同的 嗅觉感受器和突触在不同部位的分布 中心目标。因此，在再生过程中，神经元 连通性必须受到严格控制。因为这些神经元经历了 在胚胎发育过程中观察到的神经发生的不断概括， 它们代表了研究这一过程的一个很好的模型系统。 对控制神经发生的分子机制知之甚少， 并提出了从新的角度对这一过程进行研究的实验方案。 许多神经生长因子都是酪氨酸激酶，这表明 酪氨酸磷酸化在神经元生长和发育中的重要性 差异化。酪氨酸磷酸化被认为是一种机制 用来控制神经发生。一类新发现的因素，即 蛋白酪氨酸磷酸酶(PTPs)是一种独特的探测途径 神经发生。自从他们在1988年被发现以来，有超过40种不同的 PTPs已经被克隆，既有受体类型，也有细胞内类型。 对神经元中的PTPs知之甚少，也很少有底物被发现 为任何PTP确定的。酪氨酸的重要性显而易见 神经元信号转导通路中的磷酸化，很可能 PTP代表了调节这些因素的一类重要因素 小路。拟议的实验将识别和表征PTP 表达于嗅觉感觉神经元。嗅觉的再生 在神经发生过程中，神经元将被诱导建立 表达。酶活性和亚细胞定位将是 决定帮助识别可能的底物。此外， 建议通过实验来改变PTP的活性，以确定 它们在神经发生过程中的作用。利用嗅神经上皮作为 作为一个模型系统，这些实验将阐明PTPs在 神经发生和提供的信息应该适用于其他 神经系统。

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.GRANT=R03DC02094 The goal of the proposed research is to understand the molecular mechanisms controlling neurogenesis. Many pathologies involve the degeneration of the nervous system, including Alzheimer's, Huntington's and Parkinson's diseases. Similarly, spinal cord injuries can lead to paralysis due to lesions of the neuronal pathways. The majority of neurons in vertebrates are terminally differentiated and do not regenerate after damage. Understanding the processes involved in neuronal development and differentiation may ultimately yield therapies for these neuronal pathologies involving the repair or replacement of damaged neurons. The mammalian olfactory system is virtually unequaled for the study of neurogenesis in vertebrates. The olfactory sensory neurons are regenerated from stem cells throughout life. This process involves the extension of a dendrite to the mucosal surface and an axon to the olfactory bulb. The neurons from a single area of the olfactory epithelium express different populations of odorant receptors and synapse at different points on the central target. Thus, during the process of regeneration, neuronal connectivity must be tightly controlled. Because these neurons undergo a constant recapitulation of the neurogenesis observed during embryogenesis, they represent an excellent model system for the study of this process. Little is known about the molecular mechanisms controlling neurogenesis, and the experiments proposed focus on this process from a novel direction. Many neuronal growth factors are tyrosine kinases, suggesting the importance of tyrosine phosphorylation in neuronal growth and differentiation. Tyrosine phosphorylation has been proposed as a mechanism for controlling neuritogenesis. A newly identified class of factors, the protein tyrosine phosphatases (PTPs), present an unique avenue for probing neurogenesis. Since their identification in 1988, over forty different PTPs have been cloned; there are both receptor and intracellular types. Little is known about PTPs in neurons, and few substrates have been identified for any of the PTPs. With the clear importance of tyrosine phosphorylation in neuronal signal transduction pathways, it is likely that PTPs represent an important class of factors that regulate these pathways. The experiments proposed will identify and characterize PTPs expressed in the olfactory sensory neurons. Regeneration of the olfactory neurons will be induced to establish when during neurogenesis the PTPs are expressed. Enzymatic activities and subcellular localization will be determined to aid in the identification of possible substrates. Further, experiments are proposed to alter the activity of the PTPs to determine their function during neurogenesis. Using the olfactory neuroepithelium as a model system, these experiments will elucidate the role of PTPs in neurogenesis and provide information which should be applicable in other neuronal systems.