Molecular Mechanism of Neuronal Damage in Demyelinating Disorders

描述（由申请人提供）：轴突损伤是包括多发性硬化症（MS）在内的多种神经系统疾病的主要临床残疾原因。尽管在检测轴突损伤的早期迹象方面取得了相当大的进展，但对潜在的致病因素和相关的信号事件知之甚少。因此，旨在预防或修复受损轴突的治疗方法尚不可用。我们的实验室最近报道了细胞质HDAC1参与线粒体运输损伤和轴突肿胀的发生。本实验计划提出表征这种新的细胞内信号机制，并使用体外和体内模型来表征组蛋白去乙酰化酶的特定亚型在脱髓鞘疾病轴突损伤中的作用。

DESCRIPTION (provided by applicant): Axonal damage is cause of major clinical disability in a wide range of neurological disorders, including multiple sclerosis (MS). Although considerable progress has been made in the detection of the early signs of axonal damage, still very little is known about the potential causative factors and the related signaling events. Thus, therapeutic approaches aimed at preventing or repairing damaged axons are not yet available. Our laboratory has recently reported the involvement of cytoplasmic HDAC1 in the impairment of mitochondrial transport and the onset of axonal swellings. This experimental plan proposes to characterize this novel intracellular signaling mechanism and use in vitro and in vivo models to characterize the role of specific isoforms of histone deacetylases in axonal damage in demyelinating disorders. PUBLIC HEALTH RELEVANCE: Axonal damage is cause of major clinical disability in a wide range of neurological disorders, including multiple sclerosis. Although considerable progress has been made in the detection of axonal damage in demyelinating disorders still very little is known about the underlying signaling events and this is the major focus of this grant. The results of the proposed experimental plan are expected to enhance our current state of knowledge on axonal damage and lead to the identification of potential novel therapeutic targets for multiple sclerosis and other disorders characterized by axonopathy.