Targeting Endogenous Inhibitors to Enhance Spinal Axon Regeneration After Injury

项目总结 脊髓损伤通常会导致终生神经功能丧失，并伴有 发病率和死亡率。目前的项目将使用一种成熟的人类脊柱动物模型。 目的：探讨促进脊髓损伤恢复的新方法。我们的 这种方法是基于我们最近的发现，将唾液酸酶传递到 实验性脊髓损伤导致脊髓轴突生长、运动能力显著增强 恢复和心血管反射恢复。我们现在建议量化一组行为， 神经生理学和神经解剖学结果，以探索唾液酸酶单独和在 与其他疗法相结合，促进脊髓损伤后的康复。我们的建议是基于 大量数据表明，中枢神经系统轴突具有再生的能力，但 内源性轴突再生抑制物(ARI)，包括髓鞘相关的，可抑制轴突再生 残留髓鞘和软骨素上的糖蛋白(MAG)、Nogo和少突胶质细胞-髓磷脂糖蛋白 硫酸盐蛋白多糖(CSPG)对胶质瘢痕的作用。每个ARI都与轴突上的互补受体结合， 停止轴突生长。ARI及其受体的研究为阻断ARI提供了新的机会 行动和加强恢复。例如，唾液酸酶会破坏唾液酸多聚糖，这是ARI的一类 MAG的受体，以及软骨素酶ABC(ChABC)破坏CSPG。抗ARI疗法， 单独或联合使用，可促进轴突再生，改善功能恢复 脊髓损伤。我们现在建议：(I)测试唾液酸酶传递到脊柱部位的假设 大鼠脊髓挫伤可增强轴突的可塑性和/或再生，导致显著 功能恢复；(Ii)检验结合独立的抗ARI疗法，如 唾液酸酶和ChABC可相加或协同促进脊髓损伤后的恢复 挫伤，以及(Iii)使用我们对唾液酸聚糖和唾液酸酶的知识来鉴定分子 靶向治疗性唾液酸酶(S)，发现用于临床前研究的最佳唾液酸酶(S)。项目叙事 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，严重限制创伤后的恢复，并导致终身功能丧失。 值得注意的是，轴突具有再生的能力，但这种能力受到以下分子的抑制 在受伤的地方堆积。破坏或阻止这些分子可能会允许轴突再生， 极大地促进了功能恢复。

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.