Targeting Endogenous Inhibitors to Enhance Spinal Axon Regeneration After Injury

描述(由申请人提供)：脊髓损伤通常会导致终生神经功能丧失，并伴有严重的发病率和死亡率。目前的项目将使用一种成熟的人类脊髓损伤的动物模型-大鼠脊髓挫伤-来探索促进康复的新方法。我们的方法是基于我们最近的发现，将唾液酸酶输送到实验性脊髓损伤部位可以显著增强脊髓轴突生长、运动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或与其他治疗方法联合使用促进脊髓损伤后恢复的潜力。我们的建议基于大量数据，表明中枢神经系统轴突具有再生能力，但内源性轴突再生抑制物(ARI)可抑制轴突再生，包括髓鞘相关糖蛋白(MAG)、NOGO、残留髓鞘上的少突胶质细胞髓磷脂糖蛋白和胶质瘢痕上的硫酸软骨素蛋白多糖(CSPG)。每个ARI都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的作用和促进恢复提供了新的机会。例如，唾液酸酶破坏唾液酸酶，唾液酸酶破坏MAG的一类ARI受体，而软骨素酶ABC(ChABC)破坏CSPG。单独或联合应用抗ARI治疗可促进脊髓损伤后轴突再生和功能恢复。我们现在提议：(I)检验将唾液酸酶输送到大鼠脊髓挫伤后可加强轴突的可塑性和/或再生，从而导致显著功能恢复的假说；(Ii)检验将唾液酸酶和ChABC等单独的抗急性呼吸窘迫综合征疗法结合使用将额外或协同地增强脊髓挫伤后康复的假说；以及(Iii)利用我们对唾液酸聚糖和唾液酸酶的知识来确定治疗性唾液酸酶的分子靶点(S)，并发现用于临床前研究的最佳唾液酸酶(S)。与公共卫生相关：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，但在损伤部位积累的分子会抑制轴突再生。破坏或阻断这些分子可能会允许轴突再生，极大地促进功能恢复。

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.