Integrated multidisciplinary approach for analyzing diffuse myelination disorders

弥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。它们可能是由于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工作中所显示的暴露于环境毒物和化疗药物而发生的。与脱髓鞘不同的另一类疾病是其中不能形成髓鞘，导致髓鞘形成不足的那些疾病。大量的低髓鞘是对发育中的大脑的损害的结果，最常发生在儿童中。髓鞘形成不足通常与较低的智商、语言能力延迟或受损以及社交和行为异常相关，并且已被描述为与自闭症、注意力缺陷/多动障碍、精神病和精神分裂症相关。脱髓鞘和髓鞘生成不足疾病的诊断研究由于在严重临床症状发作之前难以诊断此类疾病而受到严重阻碍，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且昂贵，要么需要侵入性方法，仅产生确认结果。我们建议提供一个新的方法，允许早期诊断和干预脱髓鞘和低髓鞘疾病使用高度敏感的听觉系统作为功能读出的发展的基础。我们将描述听觉系统中靶细胞对损伤做出反应的机制的影响，并使用这种新方法来确定旨在恢复听觉神经传导的治疗干预措施的有效性，以及一般大脑中适当的髓鞘形成。

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.