Maladaptive Plasticity in Spinal Cord Injury: Cellular Mechanisms

脊髓损伤中的适应不良可塑性：细胞机制

• 批准号: 10276397
• 负责人: ADAM R FERGUSON
• 金额: $ 62.97万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10276397
• 关键词: 3-Dimensional; AMPA Receptors; Acute; Automobile Driving; Bed rest; Behavioral; Bioinformatics; Biological; Biological Assay; Chronic; Clinical; Complex; Confocal Microscopy; Data; Dendrites; Development; Electrophysiology (science); Functional disorder; Genes; Glutamate Receptor; Glutamates; Goals; H-Reflex; Hindlimb; Hindlimb Suspension; Horns; Human; Hyperreflexia; Image; Impairment; Individual; Injury; Intervention; Intractable Pain; Lesion; Limb structure; Link; Mediating; Modality; Modeling; Molecular; Molecular Profiling; Motor; Motor Neurons; Neuronal Plasticity; Neurons; Nociception; Pain; Pathway Analysis; Pathway interactions; Peripheral; Peripheral nerve injury; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phenotype; Phosphorylation; Proteins; Publishing; Quantitative Reverse Transcriptase PCR; Recovery; Recovery of Function; Reflex action; Refractory; Regulation; Rehabilitation therapy; Reproducibility; Research; Robotics; Sensorimotor functions; Serine; Shapes; Slice; Spinal; Spinal Cord; Spinal Cord Contusions; Spinal Cord Plasticity; Spinal Cord transection injury; Spinal cord injury; Stimulus; Synapses; Synaptic plasticity; Synaptosomes; Syndrome; System; Tactile; Technology; Testing; Therapeutic; Training; Transgenic Mice; Transgenic Organisms; Translations; Western Blotting; Work; base; cell injury; central pain; clinically relevant; comorbidity; epidemiology study; gain of function; genetic regulatory protein; improved; injury recovery; innovation; innovative technologies; motor disorder; mouse model; nerve injury; neurological rehabilitation; neuronal cell body; new therapeutic target; novel; patch clamp; restoration; sex; sham surgery; spasticity; trafficking; transcriptome sequencing; transcriptomics; trauma centers

PROJECT SUMMARY/ABSTRACT Spinal cord Injury (SCI) produces a devastating syndrome characterized by motor dysfunction, hyper-reflexia, spasticity, and neurogenic pain. The long-term goal of SCI therapy is to promote adaptive plasticity for restoration of function while limiting maladaptive plasticity that results in hyper-reflexia, spasticity and intractable pain. Recent research has indicated that both adaptive and maladaptive CNS plasticity can occur at the level of the spinal cord to dictate recovery of function. However, the specific conditions that promote adaptive versus maladaptive spinal plasticity in SCI are not well-understood. The central hypothesis of this R01 is that spinal cord plasticity is shaped by aberrant peripheral stimulation in the acute phase of SCI that tips plasticity toward a maladaptive form. This hypothesis has strong clinical/translational relevance, as epidemiological studies indicate that peripheral injuries and early limb disuse are prevalent comorbidities in human SCI. Up to 85% of SCI individuals presenting to level I trauma centers have peripheral injuries in addition to CNS damage. Preliminary data demonstrate that peripheral nociceptive stimulation delivered caudal to a complete SCI lesion produces maladaptive spinal plasticity that manifests as tactile hyper-reflexia and spasticity. Similar effects are observed with peripheral nerve injury or forced hindlimb disuse below SCI, and in both transection SCI and contusion SCI models. Our findings link these effects to specific alterations in glutamate receptor-mediated synaptic plasticity in the spinal ventral horn, providing a novel therapeutic target for restoration of function after SCI. The Aims of this R01 expand on the preliminary data to: 1) test mechanistic underpinnings of aberrant nociceptive stimulation below SCI (Aim 1), 2) evaluate whether similar effects occur with aberrant proprioceptive stimulation driving spinal cord central neuronal hyper- reflexia/spasticity (Aim 2), and 3) test new targets for combating maladaptive plasticity to promote adaptive recovery in SCI using transcriptomic and transgenic technologies (Aim 3). The proposed project has implications for shaping acute neuronal activity in polytraumatic SCI—a prevalent clinical presentation where CNS lesions are accompanied with peripheral injuries and protracted bedrest.

项目总结/摘要 脊髓损伤（SCI）会产生一种毁灭性的综合症，其特征是运动功能障碍、反射亢进， 痉挛和神经性疼痛。SCI治疗的长期目标是促进适应性可塑性， 恢复功能，同时限制适应不良的可塑性，导致反射过度、痉挛和 顽固性疼痛最近的研究表明，适应性和适应不良的中枢神经系统可塑性都可以发生在 脊髓的水平来决定功能的恢复。然而，促进的具体条件 SCI中的适应性与适应不良的脊柱可塑性还没有很好的理解。这个问题的核心假设是 R 01是脊髓可塑性是由SCI急性期的异常外周刺激形成的， 可塑性向适应不良的形式发展。该假设具有很强的临床/翻译相关性，因为 流行病学研究表明，外周损伤和早期肢体废用是常见的合并症， 人类脊髓损伤在I级创伤中心，高达85%的SCI患者有外周损伤， 还有CNS损伤。初步数据表明，外周伤害性刺激传递 脊髓损伤尾侧产生适应不良的脊髓可塑性，表现为触觉反射亢进 和痉挛。在周围神经损伤或脊髓损伤以下的强迫后肢废用中也观察到类似的效果， 并且在横断性SCI和挫伤性SCI模型中。我们的发现将这些影响与特定的改变联系起来， 谷氨酸受体介导的脊髓腹角突触可塑性，提供了一个新的治疗靶点 用于SCI后的功能恢复。本R 01的目的是在初步数据的基础上扩展：1）测试 SCI以下的异常伤害性刺激的机制基础（目的1），2）评估是否类似 影响发生在异常本体感受刺激驱动脊髓中枢神经元过度兴奋， 反射/痉挛（目标2），和3）测试新的目标，打击适应不良的可塑性，以促进适应性 使用转录组学和转基因技术恢复SCI（目标3）。拟议项目已 在多发性创伤性脊髓损伤中塑造急性神经元活动的意义-一种普遍的临床表现， 中枢神经系统病变伴有外周损伤和长期卧床。