Spreading Depolarizations and Perfusion in Non-traumatic Spinal Cord Injury

非创伤性脊髓损伤中的扩散去极化和灌注

• 批准号: 10480464
• 负责人: MATTHEW D BUDDE
• 金额: --
• 依托单位: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480464
• 关键词: Acute; Affect; Anatomy; Angiography; Animal Model; Animals; Area; Blood Vessels; Caring; Cell Death; Cervical; Cessation of life; Chronic; Clinical Research; Coupled; Data; Degenerative Disorder; Devices; Diagnosis; Diagnostic; Disease; Dorsal; Elderly; Electrodes; Electrophysiology (science); Ensure; Event; Evolution; Functional disorder; Glucose; Goals; Human; Implant; Individual; Injections; Injury; Intervention; Lead; Left; Lesion; Link; Magnetic Resonance Imaging; Measures; Mechanics; Metabolic; Methods; Modeling; Monitor; Neuraxis; Neurologic; Neurologic Dysfunctions; Neurons; Numbness; Operative Surgical Procedures; Outcome; Oxygen; Pain; Paralysed; Pathology; Patients; Perfusion; Process; Quality of life; Rattus; Recovery; Research; Research Personnel; Risk; Risk Factors; Rodent; Rodent Model; Role; Site; Spinal; Spinal Cord; Spinal Cord Diseases; Spinal cord damage; Spinal cord grey matter structure; Spinal cord injury; Stroke; Subdural space; Symptoms; Telemetry; Time; Tissues; Trauma; Traumatic Brain Injury; Uncertainty; United States Department of Veterans Affairs; Veterans; Well in self; aged; aging population; behavior test; bone; cell injury; clinically relevant; clinically significant; cohort; demographics; diagnostic biomarker; diagnostic value; experimental study; functional disability; gray matter; high risk; improved; improved outcome; interdisciplinary approach; military veteran; novel strategies; physical insult; pre-clinical; pressure; pressure sensor; spasticity; spinal cord compression; translational diagnostics

Cervical spondylotic myelopathy (CSM) is the most common cause of spinal cord damage in older adults. It is characterized by physical compression of the spinal cord and often progresses gradually over months to years, manifesting as weakness, numbness, and pain. Because it is a disease that disproportionately affects an aging population and leads to decreased quality of life, it has a high relevance to Veterans. Many patients with CSM have favorable outcomes after surgical intervention, but opportunities to improve outcomes through mechanistic understanding of the disease process and improved diagnostic markers would be beneficial to improve diagnosis and patient management, potentially leading to improvements in therapies. This project aims to examine the role of spreading depolarization and perfusion deficits in the context of CSM in preclinical animal models. Spreading depolarization (SD) is an abnormal wave of ionic and electrical that propagates through central nervous system tissues after an insult. While SDs have been well-established and characterized after acute physical trauma, they have not been investigated with persistent or repetitive physical compression of the spinal cord that is the hallmark of CSM. Further, SDs and underlying perfusion deficits are tightly coupled. Neurons with sufficient oxygen and glucose can recover from SDs, but neurons that are lack sufficient metabolic substrates have a high likelihood of being irreparably damaged by SDs. This project will use an animal model and electrophysiological recordings to characterize SD events in the spinal cord in the context of continuous or dynamic physical compression (Aim 1). In parallel, it will examine the perfusion deficits in the spinal cord using MRI or intraspinal pressure sensors in the context of a clinically relevant animal model of CSM with progressive spinal cord compression (Aim 2). Collectively, these studies will elucidate the mechanisms of spinal cord damage in CSM and may provide new avenues for diagnostic markers. Detecting abnormal perfusion noninvasively with MRI has a clear translational path for subsequent clinical studies of CSM patients. The team of investigators on this project have individual expertise in all of the different subject areas, and their combined multi-disciplinary approach to these studies will collectively examine a new research area with potential high clinical relevance and translational opportunities.

脊髓型颈椎病（CSM）是老年人脊髓损伤的最常见原因。这是 其特点是脊髓受到物理压迫，通常会在数月至数年内逐渐进展， 表现为无力、麻木、疼痛。因为这是一种不成比例地影响衰老的疾病 人口并导致生活质量下降，它与退伍军人有很高的相关性。许多 CSM 患者 手术干预后有良好的结果，但有机会通过机械方法改善结果 了解疾病过程和改进诊断标志物将有利于提高诊断水平 和患者管理，可能会导致治疗方法的改进。该项目旨在研究角色 临床前动物模型中 CSM 背景下扩散去极化和灌注缺陷的研究。传播 去极化 (SD) 是一种通过中枢神经系统传播的异常离子波和电波 受到侮辱后的纸巾。虽然 SD 已在急性身体创伤后得到充分证实和表征， 尚未对它们进行持续或重复的脊髓物理压迫的研究。 CSM 的标志。此外，SD 和潜在的灌注不足紧密相关。具有足够的神经元 氧和葡萄糖可以从 SD 中恢复，但缺乏足够代谢底物的神经元具有高 被 SD 造成不可挽回损坏的可能性。该项目将使用动物模型和电生理学 记录在连续或动态物理背景下表征脊髓中的 SD 事件 压缩（目标 1）。同时，它将使用 MRI 或椎管内灌注检查脊髓的灌注不足 具有渐进性脊髓的 CSM 临床相关动物模型中的压力传感器 压缩（目标 2）。总的来说，这些研究将阐明 CSM 中脊髓损伤的机制 并可能为诊断标记物提供新的途径。利用 MRI 无创检测异常灌注 为 CSM 患者的后续临床研究提供清晰的转化路径。该项目的研究团队 拥有所有不同学科领域的个人专业知识，以及他们综合的多学科方法 这些研究将共同​​检验一个具有潜在高度临床相关性和转化性的新研究领域 机会。