Promoting and understanding recovery of breathing after chronic spinal cord injury

促进和了解慢性脊髓损伤后的呼吸恢复

• 批准号: 9288741
• 负责人: Warren Joseph Alilain
• 金额: $ 34.81万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9288741
• 关键词: Acute; Adverse effects; Americas; Anatomy; Animals; Applications Grants; Behavior; Breathing; Cervical; Cervical spinal cord injury; Cervical spinal cord structure; Chondroitin ABC Lyase; Chondroitin Sulfate Proteoglycan; Chondroitinases; Chronic; Communities; Equilibrium; Excision; Extracellular Matrix; Health Care Costs; Healthcare; Hypersensitivity; Hypoxia; Injury; Intervention; Investigation; Knowledge; Lead; Learning; Length; Measures; Mechanical Ventilators; Mediating; Modeling; Motor; Motor Activity; Motor Neurons; Natural regeneration; Paralysed; Patients; Pattern; Periodicity; Play; Population; Positioning Attribute; Process; Production; Quality of life; Recovery; Recovery of Function; Regimen; Rehabilitation therapy; Research; Respiratory Diaphragm; Role; Saline; Serotonin; Spinal Cord; Spinal cord injury; Subgroup; Testing; Therapeutic Intervention; Time; Training; Translating; United States; Work; effective intervention; experimental study; functional outcomes; improved; inhibitor/antagonist; injured; insight; motor recovery; motor rehabilitation; neurotransmission; novel therapeutics; prevent; receptor; respiratory; response; response to injury; restoration; serotonin receptor; success

PROJECT SUMMARY/ABSTRACT More than 50% of all spinal cord injuries occur at the cervical level. At this level are the phrenic motor neurons which innervate the diaphragm. Therefore, injuries at this level can lead to the inability to breathe. The overall objective of this grant proposal is to examine the changes which take place chronically in the phrenic circuitry of the cord in response to cervical spinal cord injury and investigate and optimize potential therapies that can restore breathing long after injury. Through these studies, an effective intervention can be translated to a significant population of the spinal cord injured community. In this proposal we will utilize chronic cervical spinal cord-hemisected animals which have half of the diaphragm paralyzed. In our earlier studies we observed that enzymatic (chondroitinase ABC) removal of extracellular matrix molecules, called chondroitin sulfate proteoglycans, which block plasticity, regeneration, and sprouting, led to restoration of function of the once paralyzed hemidiaphragm when administered at or near the time of injury. Recovered diaphragmatic activity was rhythmic and synchronized. In stark contrast, when the spinal cord of chronically injured animals was stimulated with chondroitinase ABC and intermittent hypoxia training, chaotic and unstructured activity resulted, suggesting slowly developing and potentially maladaptive responses to injury. However, the use of chondroitinase alone at chronic stages can promote normal rhythm and dramatically enhance properly patterned functional recovery. This grant proposal seeks to: 1) understand the time course and carefully describe the maladaptive processes that take place; 2) understand the mechanisms underlying the production of this newly discovered atypical activity at chronic time points; and 3) learn how to overcome these negative responses to injury so that interventions and rehabilitative strategies can become more effective, thereby leading to improved functional outcomes. Overall, these studies will provide insight on the basic mechanisms that underlie maladaptive, as well as functionally beneficial plasticity that can lead to robust functional respiratory motor recovery at chronic stages of spinal cord injury.

项目概要/摘要 超过 50% 的脊髓损伤发生在颈椎水平。在这个水平是膈运动 支配膈肌的神经元。因此，这种程度的伤害可能会导致呼吸困难。 该赠款提案的总体目标是检查长期发生的变化 脊髓膈回路响应颈脊髓损伤并研究和优化潜力 可以在受伤后很长时间内恢复呼吸的疗法。通过这些研究，可以采取有效的干预措施 转化为脊髓损伤社区的大量人口。在本提案中，我们将利用 慢性颈脊髓半切动物，其一半膈肌瘫痪。在我们之前的 研究中我们观察到酶（软骨素酶 ABC）去除细胞外基质分子，称为 硫酸软骨素蛋白多糖可阻止可塑性、再生和发芽，从而恢复 在受伤时或接近受伤时施用时，曾经瘫痪的半膈的功能。已恢复 膈肌活动是有节奏且同步的。形成鲜明对比的是，当脊髓长期处于 受伤动物接受软骨素酶ABC刺激和间歇性缺氧训练，混乱和 结果导致了非结构化活动，表明对伤害的反应发展缓慢且可能存在适应不良。 然而，在慢性阶段单独使用软骨素酶可以促进正常节律并显着 增强正确模式的功能恢复。该拨款提案旨在：1）了解时间进程 并仔细描述发生的适应不良过程； 2）了解底层机制 这种新发现的非典型活动在慢性时间点的产生； 3）学习如何克服 这些对伤害的负面反应使得干预和康复策略可以变得更加重要 有效，从而改善功能结果。总的来说，这些研究将提供关于 适应不良的基本机制，以及功能上有益的可塑性，可以导致强大的 脊髓损伤慢性阶段的功能性呼吸运动恢复。