Targeting Endogenous Inhibitors to Enhance Spinal Axon Regeneration After Injury

靶向内源性抑制剂以增强损伤后脊髓轴突再生

基本信息

批准号：
8214620
负责人：
RONALD L SCHNAAR
金额：
$ 35.14万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8214620
关键词：
Animal Model Astrocytes Axon Behavior Behavioral Binding Biology Brachial plexus structure Cardiovascular system Chondroitin ABC Lyase Chondroitin Sulfate Proteoglycan Cicatrix Contusions Critiques Data Environment Enzymes Evaluation Family Future Gangliosides Health Human Implant In Vitro Infusion procedures Injury Knowledge Label Life Locomotor Recovery Mediating Modeling Molecular Molecular Target Molecular Weight Morbidity - disease rate Motor Neurons Myelin Myelin Associated Glycoprotein Natural regeneration Nerve Neuraminidase Neuraxis Neurons Outcome Peptides Phosphatidylinositols Phospholipase C Physiological Polysaccharides Publishing Rattus Reagent Recovery Recovery of Function Reflex action Research Project Grants Residual state Sialoglycoproteins Side Signal Transduction Signaling Molecule Site Specificity Spinal Spinal Cord Spinal Cord Contusions Spinal cord injury Spinal nerve structure Study Section Testing Therapeutic Time Treatment Efficacy United States National Institutes of Health autonomic reflex axon regeneration base behavior test cell type central nervous system injury improved in vivo inhibitor/antagonist injured loss of function mortality nerve injury neurophysiology neurotrophic factor novel oligodendrocyte-myelin glycoprotein preclinical study receptor regenerative sialoglycolipids therapeutic development therapeutic target

项目摘要

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.

描述（由申请人提供）：脊髓损伤通常会导致神经功能的终生丧失，并伴有深远的发病率和死亡率。当前的项目将使用公认的动物模型来用于人脊髓损伤 - 大鼠中的脊髓挫伤 - 研究增强恢复的新方法。我们的方法是基于我们最近发现的，即将酶唾液酸酶传递到实验性脊髓损伤部位导致脊柱轴突出生，运动型恢复和心血管反射恢复的显着增强。现在，我们建议量化一系列行为，神经生理学和神经解剖学结果，以探索单独并与其他治疗结合使用唾液酸酶的潜力，以增强脊髓损伤后的恢复。 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）在神经胶质疤痕上。每个ARI都与轴突上的互补受体结合，停止轴突的生长。对ARI和ARI受体的知识为阻止ARI行动并增强恢复提供了新的机会。例如，唾液酸酶破坏了唾液酸聚糖，MAG的一类ARI受体，而软骨软骨酶ABC（CHABC）摧毁了CSPG。抗ARI疗法单独或结合使用，可以增强轴突再生并改善脊髓损伤后的功能恢复。现在，我们建议：（i）检验以下假设：唾液酸酶在大鼠中递送到脊髓挫伤部位将增强轴突的可塑性和/或再生，从而导致显着的功能恢复； (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. 公共卫生相关性：包括脊髓在内的成熟中枢神经系统对轴突再生是绝大多数的抑制作用，严重限制了创伤性损伤后的恢复，并导致终生的功能丧失。值得注意的是，轴突具有再生能力，但由于在损伤部位积累的分子而抑制了轴突。破坏或阻断这些分子可能会使轴突再生，从而大大增强功能恢复。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sialidase, chondroitinase ABC, and combination therapy after spinal cord contusion injury.

DOI：
10.1089/neu.2012.2353
发表时间：
2013-02
期刊：
Journal of neurotrauma
影响因子：
4.2
作者：
A. Mountney;M. Zahner;Elizabeth R. Sturgill;Christopher J Riley;J. W. Aston;M. Oudega;L. Schramm;Andrés Hurtado;R. Schnaar
通讯作者：
A. Mountney;M. Zahner;Elizabeth R. Sturgill;Christopher J Riley;J. W. Aston;M. Oudega;L. Schramm;Andrés Hurtado;R. Schnaar

Brain gangliosides in axon-myelin stability and axon regeneration.