Role of Cellular Activity in Spinal Cord Injury Recovery

描述（由申请人提供）： 脊髓再生需要受损的神经元存活，重新生长轴突， 并与合适的目标重新建立联系由于这些事件中有许多是相关的 在脊髓发育过程中必须发生的事情，它可能有助于使用 为了恢复运动功能， 脊髓损伤（SCI）。许多研究都集中在抗炎 类固醇和谷氨酸拮抗剂，以最大限度地减少神经元死亡， 髓鞘相关糖蛋白（MAG）和Nogo-A等因素，以克服 轴突生长的抑制;但较少的研究已经解决了这个问题， 重新建立功能性和适当的突触连接。除了 显然需要重新建立适当的联系， 运动，重要的是不要促进随机增长和连接 因为适应不良的功能可能导致神经性疼痛， example. 发育研究表明，细胞去极化（活动）是 在胎儿期建立适当运动功能的重要过程 发展脊髓运动网络的形成，最初 突触发生，连接的完善，细胞存活，以及 肌肉目标的成熟都被认为至少部分取决于 活动因此，该试点项目的总体目标是确定 细胞活动如何影响SCI恢复的机制。两大目标 该建议的主要内容是：（L）开发一种新的基因修饰小鼠品系， 运动神经元的活动可以被打开和关闭，以及（2.）使用 从轻度挫伤恢复的小鼠的遗传学和药理学方法 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SCI恢复， 可以提供对期望的细胞和分子靶点的深入了解， 促进功能性运动重建的药物 SCI后的电路

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.