Role of Cellular Activity in Spinal Cord Injury Recovery

描述(由申请人提供)： 脊髓再生需要损伤的神经元存活，重新生长轴突， 并与适当的目标重新建立联系。由于这些事件中的许多都与 对于脊髓发育过程中必须发生的事情，它可能会有所帮助 恢复运动功能的发展策略 脊髓损伤(SCI)。许多研究都集中在抗炎方面。 类固醇和谷氨酸拮抗剂，以减少神经元死亡，并抑制 髓鞘相关糖蛋白(MAG)和Nogo-A等因子需要克服 轴突生长的抑制；但较少的研究解决了 重建功能性和适当的突触连接。除了……之外 显然需要重新建立适当的联系，以协调 移动，重要的是不要促进随意的增长和连接 因为适应不良可能会导致神经病理性疼痛，例如 举个例子。 发育研究表明，细胞去极化(活性)是一种 胎儿期建立适当运动功能的重要环节 发展。脊髓运动网络的形成，最初 突触发生、连通性的改善、细胞存活以及 肌肉靶点的成熟都被认为至少部分取决于 活动。因此，这一试点项目的总体目标是明确 从机制上讲，细胞活动如何影响脊髓损伤的恢复。两大目标 这项建议的内容是：(L)在中国培育一种新型的转基因小鼠品系 运动神经元的活动可以被开启和关闭，以及(2)使用 轻度挫伤小鼠康复过程中的遗传学和药理学研究 SCI精确定义活动在重建、运动中的作用 功能。这些研究应该确定活动如何影响脊髓损伤的恢复，以及 可能提供对理想的细胞和分子靶点的洞察 促进功能性运动功能改变的药理作用药物 跟踪SCI的电路。

DESCRIPTION (provided by applicant): Spinal cord regeneration requires injured neurons to survive, re-grow axons, and reconnect with appropriate targets. Since many of these events are related to what must occur during spinal cord development, it may be helpful to use developmental strategies in order to restore locomotor function following spinal cord injury (SCI). Numerous studies have focused on anti-inflammatory steroids and glutamate antagonists, to minimize neuronal death, and inhibitory factors such as myelin-associated glycoprotein (MAG) and Nogo-A, to overcome the inhibition of axon growth; but less research has addressed the problem of reestablishing functional and appropriate synaptic connections. In addition to the obvious need to reestablish appropriate connections to mediate coordinated locomotion, it is important not to promote random growth and connections because maladaptive function could arise resulting in neuropathic pain, for example. Developmental studies have implicated cellular depolarization (activity) as an important process in establishing appropriate locomotor function during fetal development. The formation of spinal locomotor networks, initial synaptogenesis, refinement of connectivity, cell survival, as well as maturation of muscle targets are all thought to depend, at least in part, on activity. Therefore, the overall aim of this pilot project is to define mechanistically how cellular activity affects SCI recovery. The two major goals of this proposal are: (L) to develop a novel genetically-modified mouse line in which the activity of motor neurons can be switched ON and OFF, and (2.) to use genetic and pharmacological approaches in mice recovering from mild contusive SCI to precisely define the role of activity in reestablishing, locomotor function. These studies should define how activity influences SCI recovery, and may provide insight into desirable cellular and molecular targets for pharmacalogical agents that promote the reformation of functional locomotor circuitry following SCI.