Targeting Endogenous Inhibitors to Enhance Spinal Axon Regeneration After Injury

项目摘要 脊髓损伤通常会导致终身神经功能丧失，伴随着严重的神经损伤。 发病率和死亡率。目前的项目将使用一个完善的动物模型， 脊髓损伤大鼠脊髓挫伤研究新的方法，以提高恢复。我们 这种方法是基于我们最近的发现，即将唾液酸酶递送到 实验性脊髓损伤导致脊髓轴突生长、运动能力显着增强 恢复和心血管反射恢复。我们现在建议量化一系列的行为， 神经生理学和神经解剖学结果，以探索唾液酸酶单独使用和 结合其他治疗，以促进脊髓损伤后的恢复。我们的建议是基于 大量的数据表明，中枢神经系统轴突有再生的能力，但 通过内源性轴突再生抑制剂（ARI），包括髓鞘相关的 糖蛋白（MAG）、Nogo和少突胶质细胞-髓鞘糖蛋白对残余髓鞘和软骨素的影响 硫酸蛋白聚糖（CSPG）的胶质瘢痕。每个ARI与轴突上的互补受体结合， 阻止轴突生长对ARI和ARI受体的了解为阻断ARI提供了新的机会 行动，促进复苏。例如，唾液酸酶破坏唾液酸聚糖，一类ARI CSPG是MAG的受体，而软骨素酶ABC（ChABC）破坏CSPG。抗ARI疗法， 单独地或组合地，可以增强轴突再生并改善术后功能恢复。 脊髓损伤我们现在提出：（i）测试唾液酸酶递送到脊髓损伤部位的假设， 大鼠脊髓挫伤后，轴突可塑性和/或再生增强， 功能恢复;（ii）检验联合独立抗ARI治疗的假设，如 唾液酸酶和ChABC将导致脊髓损伤后恢复的累加或协同增强。 挫伤，以及（iii）利用我们对唾液酸聚糖和唾液酸酶的了解来鉴定分子 靶点的治疗性唾液酸酶和发现最好的唾液酸酶的临床前研究。项目叙述 成熟的中枢神经系统，包括脊髓，对轴突具有压倒性的抑制作用， 再生，严重限制创伤性损伤后的恢复，并导致终身功能丧失。 值得注意的是，轴突有再生的能力，但被分子抑制， 在损伤部位积聚。破坏或阻断这些分子可以使轴突再生， 大大促进了功能恢复。

PROJECT SUMMARY Spinal cord injury typically results in life-long loss of nerve function accompanied by profound morbidity and mortality. The current project will use a well-established animal model for human spinal cord injury ¿ spinal cord contusion in the rat ¿ to investigate novel ways to enhance recovery. Our approach is based on our recent discovery that delivery of the enzyme sialidase to the site of experimental spinal cord injuries results in significant enhancements in spinal axon outgrowth, locomotor recovery, and cardiovascular reflex recovery. We now propose to quantify a battery of behavioral, neurophysiological and neuroanatomical outcomes to explore the potential of sialidase, alone and in combination with other treatments, to enhance recovery after spinal cord injury. Our proposal is based on a wealth of data indicating that central nervous system axons have the capacity to regenerate, but are inhibited from doing so by endogenous axon regeneration inhibitors (ARI's), including myelin-associated glycoprotein (MAG), Nogo, and oligodendrocyte-myelin glycoprotein on residual myelin and chondroitin sulfate proteoglycan (CSPG) on the glial scar. Each ARI binds to complementary receptors on axons, halting axon outgrowth. Knowledge of ARI's and ARI receptors provides new opportunities to block ARI actions and enhance recovery. For example, the enzyme sialidase destroys sialoglycans, a class of ARI receptors for MAG, and the enzyme chondroitinase ABC (ChABC) destroys CSPG. Anti-ARI therapies, individually or in combination, may enhance axon regeneration and improve functional recovery after spinal cord injury. We now propose to: (i) Test the hypothesis that sialidase delivery to the site of a spinal cord contusion injury in the rat will enhance axon plasticity and/or regeneration, resulting in significant functional recovery; (ii) Test the hypothesis that combining independent anti-ARI therapies, such as sialidase and ChABC, will result in additive or synergistic enhancements of recovery after spinal cord contusion injury, and (iii) Use our knowledge of sialoglycans and sialidases to identify the molecular target(s) of therapeutic sialidase and discover the best sialidase(s) for preclinical studies. PROJECT NARRATIVE The mature central nervous system, including the spinal cord, is overwhelmingly inhibitory for axon regeneration, severely limiting recovery after traumatic injury and resulting in life-long loss of function. Remarkably, axons have the ability to regenerate, but are inhibited from doing so by molecules that accumulate at injury sites. Destroying or blocking these molecules may permit axons to regenerate, greatly enhancing functional recovery.