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: 10449363
• 负责人: ADAM R FERGUSON
• 金额: $ 61.02万
• 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/10449363
• 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.

项目摘要/摘要 脊髓损伤（SCI）产生一种毁灭性综合征，其特征是运动功能障碍，超反射， 痉挛和神经源性疼痛。 SCI治疗的长期目标是促进自适应可塑性 恢复功能的同时限制适应不良的可塑性，导致超反射，痉挛和 顽固的疼痛。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可能发生在 脊髓的水平决定了功能的恢复。但是，促进的特定条件 SCI中的自适应与适应不良的脊柱可塑性并不理解。中心假设 R01是脊髓可塑性是由SCI急性阶段异常的外周刺激所塑造的 适应不良形式的可塑性。该假设具有强大的临床/转化相关性， 流行病学研究表明，周围损伤和早期肢体废弃是普遍的合并症 人科学。多达85％的SCI个体出现到I级创伤中心的SCI个人有外围伤害 加上CNS损坏。初步数据表明，传递的外周伤害刺激 完整的科幻病变会产生不良适应性的脊柱可塑性，表现为触觉超反射症 和痉挛。通过外周神经损伤或强迫后肢在SCI以下观察到类似的影响， 在翻译SCI和挫伤科学模型中。我们的发现将这些效果与特定更改联系起来 脊柱腹角中的谷氨酸受体介导的合成可塑性，提供了一种新型的热靶 用于恢复SCI后功能。此R01的目的扩展了初步数据至：1）测试 SCI以下（AIM 1），2）评估异常伤害刺激的机械基础 效果发生在异常的本体感受刺激驱动脊髓中央神经元超高 - 反射/痉挛（AIM 2）和3）测试新目标，以抗击适应不良的可塑性以促进适应性 使用转录组和转基因技术在SCI中恢复（AIM 3）。拟议的项目有 对多发性科幻中急性神经元活性的影响 - 普遍的临床表现 中枢神经系统病变伴有外围损伤和持久的床架。