Molecular Mechanism of Neuronal Damage in Demyelinating Disorders

描述（由申请人提供）：轴突损伤是多种神经系统疾病（包括多发性硬化症（MS））的主要临床残疾原因。虽然在轴突损伤的早期信号检测方面已经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仍然知之甚少。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HDAC1参与线粒体转运的损伤和轴突损伤的发生。该实验计划提出了表征这种新的细胞内信号传导机制，并使用体外和体内模型来表征组蛋白脱乙酰酶的特定亚型在脱髓鞘疾病中轴突损伤中的作用。 公共卫生相关性：轴突损伤是多种神经系统疾病（包括多发性硬化症）的主要临床残疾原因。虽然在脱髓鞘疾病中轴突损伤的检测方面已经取得了相当大的进展，但对潜在的信号传导事件仍然知之甚少，这是该基金的主要重点。拟议的实验计划的结果，预计将提高我们目前的知识状态轴突损伤，并导致识别潜在的新的治疗目标多发性硬化症和其他疾病的轴突病变的特点。

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.