Integrated multidisciplinary approach for analyzing diffuse myelination disorders

漫漫性脱髓鞘疾病影响了超过25万的美国人，并与广泛的临床表现有关。慢性酒精中毒和营养不良、炎症过程、病毒感染、缺氧缺血性损伤、局灶性抑郁、代谢功能障碍，以及我们在自己的研究中所显示的，暴露于环境毒物和化疗药物会导致这些疾病。另一类不同于脱髓鞘的疾病是那些无法形成髓磷脂的疾病，导致髓鞘形成不足。大量的髓鞘退化是发育中的大脑受到损伤的结果，最常发生在儿童身上。髓鞘发育低下通常与低智商、语言能力延迟或受损以及社交和行为异常有关，并被描述为与自闭症、注意力缺陷/多动障碍、精神病和精神分裂症有关。脱髓鞘和低髓鞘疾病的诊断研究受到严重阻碍，因为难以在出现严重临床症状之前诊断出这类疾病，因为目前的诊断工具，如磁共振成像或组织病理学分析，要么灵敏度有限，价格昂贵，要么需要侵入性方法，只能产生确证性结果。我们建议为开发一种新方法提供基础，该方法可以使用高度敏感的听觉系统作为功能读出器，对脱髓鞘和低髓鞘疾病进行早期诊断和干预。我们将描述听觉系统中靶细胞对损伤的反应机制的影响，并使用这种新方法来确定旨在恢复听觉神经传导和大脑中正常髓鞘形成的治疗干预的效果。

Diffuse demyelination disorders affect more than one-quarter million of Americans and are associated with a wide range of clinical manifestations. They can occur due to chronic alcoholism and malnourishment, inflammatory processes, viral infection, hypoxic-ischemic injury, focal depression, metabolic dysfunction and as we show in our own work, by exposure to environmental toxicants and chemotherapeutic agents. Another class of diseases that are distinct from demyelination are those in which there is a failure to form myelin, resulting in hypomyelination. A large number of hypomyelinations are a consequence of insults to the developing brain and most frequently occur in children. Hypomyelination is often associated with lower IQ, delayed or impaired verbal skills and social and behavioral abnormalities and has been described to be associated with autism, attention deficit/hyperactivity disorder, psychosis and schizophrenia. The diagnostic study of demyelinating and hypomyelinating disorders is severely hampered by the difficulty to diagnose such diseases prior to the onset of severe clinical symptoms, as current diagnostic tools such as magnetic resonance imaging or histopathological analysis are either limited in their sensitivity and costly, or require invasive methods, that generate only confirmatory results. We propose to provide the basis for the development of a new approach that allows the early diagnosis and intervention for de- and hypomyelinating disorders using the highly sensitive auditory system as a functional readout. We will characterize the impact of mechanism by which target cells in the auditory system respond to the insults and use this new approach to determine the efficacy of therapeutic interventions that are designed to restore auditory nerve conduction specifically and proper myelination in the brain in general.