Targeting Endogenous Inhibitors to Enhance Spinal Axon Regeneration After Injury

描述（由申请人提供）：脊髓损伤通常导致终身神经功能丧失，并伴有严重的发病率和死亡率。目前的项目将使用一个成熟的人类脊髓损伤动物模型-大鼠脊髓挫伤-来研究促进恢复的新方法。我们的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的部位导致脊髓轴突生长、运动恢复和心血管反射恢复的显著增强。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使用和与其他治疗方法联合使用的潜力，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能力再生，但抑制这样做的内源性轴突再生抑制剂（ARI），包括髓鞘相关糖蛋白（MAG），Nogo，和少突胶质细胞髓鞘糖蛋白残留髓鞘和硫酸软骨素蛋白聚糖（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。ARI和ARI受体的知识提供了新的机会，以阻止ARI的行动和促进恢复。例如，唾液酸酶破坏唾液酸聚糖，一类MAG的ARI受体，而软骨素酶ABC（ChABC）破坏CSPG。抗ARI治疗，单独或联合使用，可以增强轴突再生，改善脊髓损伤后的功能恢复。我们现建议：（i）测试以下假设：将唾液酸酶递送至大鼠的脊髓挫伤损伤部位将增强轴突可塑性和/或再生，导致显著的功能恢复;（ii）检验组合独立的抗ARI疗法（例如唾液酸酶和ChABC）将导致脊髓挫伤后恢复的累加或协同增强的假设，和（iii）利用我们对唾液酸聚糖和唾液酸酶的了解来鉴定治疗性唾液酸酶的分子靶标，并发现用于临床前研究的最佳唾液酸酶。 公共卫生相关性：成熟的中枢神经系统，包括脊髓，对轴突再生具有压倒性的抑制作用，严重限制了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，但被损伤部位积累的分子抑制。破坏或阻断这些分子可以使轴突再生，大大增强功能恢复。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.