Sympathetic Function in Neural Injuries

神经损伤中的交感功能

• 批准号: 10494147
• 负责人: Patricia J Ward
• 金额: $ 23.42万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10494147
• 关键词: Acute; Aging; Anatomy; Animals; Axon; Basic Science; Biochemical; Bioenergetics; Biogenesis; Biological Sciences; Biology; Bioluminescence; Brain; Case Study; Chronic Fatigue Syndrome; Clinical; Clinical Trials; Development; Dose; Electric Stimulation; Electrophysiology (science); Exercise; Functional disorder; Genetic; Goals; Guidelines; Health; Image; Immobilization; Individual; Injury; Ion Channel; Knowledge; Laboratories; Lasers; Leg; Lesion; Light; Limb structure; Luciferases; Membrane Protein Traffic; Mentors; Metabolic; Metabolic Control; Mitochondria; Motor; Motor Neurons; Muscle; Muscle Fibers; Muscle Weakness; Muscular Atrophy; Myasthenia Gravis; Natural regeneration; Nerve; Nerve Tissue; Nervous System Trauma; Neuromuscular Diseases; Neuromuscular Junction; Neurons; Neurosciences; Ohio; Operative Surgical Procedures; Outcome Measure; Pain; Paralysed; Pathologic; Patients; Peripheral; Peripheral nerve injury; Persons; Pre-Clinical Model; Presynaptic Terminals; Process; Protein Biosynthesis; Proteins; Quality of life; Recovery; Recovery of Function; Regenerative research; Rehabilitation therapy; Research; Research Personnel; Respiration; Role; Scientist; Sensory; Skeletal Muscle; South Carolina; Spinal Cord; Spinal Cord Lesions; Spinal cord injury; Spinal nerve structure; Structure; Sympathetic Nervous System; Synapses; Synaptic Membranes; Testing; Therapeutic Intervention; Thoracic spinal cord structure; Training; Transgenic Mice; Translational Research; Traumatic injury; United States; Universities; Wages; Work; axon growth; axon injury; axon regeneration; base; career; comorbidity; compliance behavior; conditioning; disability; effectiveness evaluation; experimental study; functional outcomes; improved; injured; innovative technologies; life time cost; locomotor deficit; mitochondrial dysfunction; motor axon regeneration; motor control; muscle strength; nerve injury; nerve repair; nerve supply; nervous system disorder; neuromuscular; new technology; novel; optogenetics; prevent; receptor; recruit; regenerative; response; sarcopenia; sciatic nerve; spinal cord repair; tool; translational potential

Peripheral nerve injuries are common with more than 200,000 new cases reported each year in the United States alone. Only about 10% of these individuals regain much function. There are 17,730 new U.S. spinal cord injuries annually, and the lifetime costs can reach $5 million per person (not including lost wages). Nerve injury and especially spinal cord injury significantly impact long-term quality of life, and most injured individuals seek continued treatments for associated disabilities and pain. The most common explanation for poor functional outcomes is the slow and inefficient process of axon regeneration. Axons within the spinal cord and nerve consist of motor, sensory, and sympathetic axons, which undergo plasticity after injury. A critical knowledge gap in neuroscience is understanding the purpose of sympathetic axon terminals within the neuromuscular synapse, how sympathetic axons associated with neuromuscular junctions respond to neural injuries, and what their contribution is to functional recovery or dysfunction. Preliminary evidence suggests that the sympathetic innervation of neuromuscular junctions can modulate mitochondrial respiration and biogenesis, synaptic stability, and muscle strength as well as control the muscle response to exercise and activity. The overarching hypothesis of this K01 proposal is that sympathetic neurons are required for the functional and metabolic stability of the neuromuscular unit in normal and pathological conditions. We will first test the necessity and sufficiency of sympathetic nerve activity on metabolic and motor control using a novel technology, BioLuminescent OptoGenetics (BL-OG) in normal, uninjured animals. My research has shown that exercise and neuronal activity strikingly enhance peripheral axon regeneration and significantly improves functional recovery following complete nerve and spinal cord injuries in preclinical models. However, while clinician scientists recognize the importance of exercise to promote axon regeneration and metabolic health, the translational potential of exercise has many limitations. Many patients are not candidates for exercise due to co-morbidities that preclude rehabilitation, necessary immobilization of a limb following surgical nerve repair, unknown dose requirement of exercise, and low patient compliance. Further limitations are that nearly 70% of the skeletal muscle of people with a spinal cord injury is paralyzed, and there are no guidelines for electrically induced exercise of paralyzed muscle. Experimental evidence also shows that sympathetic axon regrowth may even be inhibited by certain types of treatments, such as electrical stimulation. Thus, other goals of this work are to investigate whether increasing sympathetic activity 1) promotes or inhibits sympathetic axon regeneration after peripheral nerve injury, and 2) can rescue the muscle bioenergetic and motor control deficits after spinal cord injury.

周围神经损伤很常见，每年在曼联报告的200,000多例新病例 一个人。这些人中只有大约10％的人重新获得了很多功能。有17,730个新的美国脊柱 绳索受伤每年受伤，终生费用可以达到每人500万美元（不包括工资损失）。神经 损伤，尤其是脊髓损伤显着影响长期生活质量，大多数受伤的人 寻求持续治疗相关的残疾和痛苦。穷人最常见的解释 功能结果是轴突再生的缓慢和效率低下的过程。脊髓内的轴突和 神经由电动机，感觉和交感神经轴突组成，后者在受伤后经历可塑性。批判 神经科学中的知识差距是理解同情轴突终端的目的 神经肌肉突触，与神经肌肉连接相关的交感神经轴突如何响应神经 伤害及其对功能恢复或功能障碍的贡献。初步证据表明 神经肌肉连接的交感神经能够调节线粒体呼吸和 生物发生，突触稳定性和肌肉力量，并控制肌肉对运动的反应 活动。该K01提案的总体假设是，需要交感神经元 在正常和病理条件下神经肌肉单位的功能和代谢稳定性。我们将首先 使用新颖 正常的，未受伤的动物中的技术，生物发光光学遗传学（BL-OG）。我的研究表明 运动和神经元活动显着增强外围轴突再生，并显着改善 临床前模型中完全神经和脊髓损伤后的功能恢复。但是， 临床医生认识到运动对促进轴突再生和代谢健康的重要性， 锻炼的翻译潜力有许多局限性。许多患者不是应付锻炼的候选人 对于排除康复的合并症，手术神经修复后有必要固定肢体， 不明剂量的运动要求和患者依从性较低。进一步的限制是将近70％ 患有脊髓损伤的人的骨骼肌瘫痪，没有电准则 诱发瘫痪的肌肉。实验证据还表明，交感神经轴突再生 甚至可能被某些类型的治疗方法（例如电刺激）抑制。因此，其他目标 工作是研究增加交感神经的增加1）促进还是抑制交感神经轴突 周围神经损伤后的再生，2）可以挽救肌肉生物能和运动控制缺陷 脊髓损伤后。