Re-expression of L1 CAM Following Spinal Cord Injury

描述(由申请人提供)： L1是一种轴突细胞黏附分子(CAM)，在 轴突在发育过程中不断增长，但在成年后下降到较低水平。vt.LL CaM在哺乳动物中高度保守，相关分子在多种细胞中都有发现 物种，这表明它在轴突寻路和 丛生。L1由嗅鞘胶质细胞(OEG)和雪旺细胞表达 细胞，两者都促进轴突再生。此外，LL是 在海马区再生轴突中重新表达。因此，ll是一个 粘附型分子的极佳候选者，对 再生的脊髓轴突。具体目标1是确定脊柱上的 一组表达L1的GABA能连合神经元的靶标 它们轴突的表面。随后的实验将检查轴突 这些连合神经元在LL基因敲除小鼠中的路径发现。具体目标2 试图确定在成年轴突再生新的过程中，LL是否重新表达 脊髓损伤后的过程。在完成了一次完整的中胸手术后 出生后第5天的脊髓横断，我们有初步数据表明 L1在损伤3的吻侧和尾侧轴突中重新表达 受伤后几个月。我们将刻画L1在轴突上的时间表达 相对于受伤后的时间提供有关潜在的信息 脊髓损伤后轴突萌发。此外，我们将测试是否训练脊椎 脊髓踏步模式的横断动物将改变L1的水平 损伤轴突上的表达。在特定目标3中，一种OEG移植模型 将被用来确定提升的感觉轴突是否能够投射到 它们的目标，如果上升和下降再生轴突 当它们穿过横断点时，重新表达LLCAM。脊椎横断动物 将被移植到表达LL的OEG细胞，而对照组将被 注入了介质。这种OEG移植模型已经被其他人证明 显著改善脊髓损伤成年动物的自主运动功能。我们的 长期目标是开发一种脊髓损伤的再生模型，以恢复 来自连合神经元的上升投射。

DESCRIPTION (provided by applicant): L1 is an axonal cell adhesion molecule (CAM) that is highly expressed on growing axons during development but decreases to low levels by adulthood. Ll CAM is highly conserved in mammals, and related molecules are found in diverse species, suggesting a conservation of its function in axonal pathfinding and fasciculation. L1 is expressed by olfactory ensheathing glia (OEG) and Schwann cells, both of which facilitate axon regeneration. In addition, Ll is re-expressed on regenerating axons in the hippocampal formation. Thus, Ll is an excellent candidate for an adhesion type molecule of critical importance to regenerating spinal cord axons. Specific Aim 1 is to determine the supraspinal target of a population of GABAergic commissural neurons that express Ll on the surface of their axons. Subsequent experiments will examine the axonal pathfinding of these commissural neurons in Ll knockout mice. Specific Aim 2 seeks to determine if Ll is re-expressed on adult axons as they regenerate new processes after spinal cord injury (SCI). Following a complete midthoracic spinal cord transection at postnatal day 5, we have preliminary data suggesting that Ll is re-expressed in axons both rostral and caudal to the lesion three months post injury. We will characterize the temporal expression of Ll on axons relative to the time post injury to provide information regarding potential axon sprouting after SCI. Furthermore, we will test if training spinal transected animals in spinal stepping patterns will change the level of Ll expression on lesioned axons. In Specific Aim 3, an OEG transplantation model will be used to determine if ascending sensory axons are able to project to their targets and if ascending and descending regenerating axons will re-express Ll CAM as they cross the transection site. Spinal transected animals will be transplanted with Ll-expressing OEG cells, whereas the controls will be injected with media. This OEG transplantation model has been shown by others to dramatically improve voluntary motor function in adult animals with SCI. Our long term goal is to develop a regeneration model for SCI that restores the ascending projections from commissural neurons.