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: 10596632
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10596632
• 关键词: Acute; Affect; Anatomy; Angiography; Animal Model; Animals; Area; Blood Vessels; Caring; Cell Death; Central Nervous System; Cervical; Cessation of life; Chronic; Clinical Research; Coupled; Data; Degenerative Disorder; Devices; Diagnosis; Diagnostic; Disease; Dorsal; Elderly; Electrodes; Electrophysiology (science); Emotional; Ensure; Event; Evolution; Functional disorder; Glucose; Goals; Human; Implant; Individual; Injections; Injury; Intervention; Left; Lesion; Link; Magnetic Resonance Imaging; Measures; Mechanics; Metabolic; Methods; Modeling; Monitor; Neurologic; Neurologic Dysfunctions; Neurons; Numbness; Operative Surgical Procedures; Outcome; Oxygen; Pain; Paralysed; Pathology; Patients; Perfusion; Polymers; 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; Vertebral column; Veterans; Well in self; aged; aging population; behavior test; bone; cell injury; clinical translation; 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; translational potential

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.

宫颈脊柱脊髓病（CSM）是老年人脊髓损伤的最常见原因。这是 以脊髓的物理压缩为特征，并且经常在数月到几年中逐渐发展 表现为弱点，麻木和痛苦。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，与退伍军人具有很高的相关性。许多CSM患者 手术干预后具有有利的结果，但有机会通过机械 了解疾病过程和改进的诊断标志物将有益于改善诊断 和患者管理，有可能改善疗法。该项目旨在检查角色 在临床前动物模型中CSM中散布去极化和灌注不足的散布。蔓延 去极化（SD）是一个异常的离子和电气，它通过中枢神经系统传播 侮辱后的组织。虽然SD在急性身体创伤后已建立了良好和表征，但 尚未对脊髓进行持续或重复的物理压缩进行调查，这是 CSM的标志。此外，SD和潜在的灌注不足是紧密耦合的。神经元足够 氧气和葡萄糖可以从SD中恢复，但是缺乏足够代谢底物的神经元具有很高 被SD不可避免地损坏的可能性。该项目将使用动物模型和电生理学 在连续或动态物理的背景下，记录以表征脊髓中的SD事件 压缩（目标1）。同时，它将使用MRI或脊柱内检查脊髓中的灌注不足 在具有进行性脊髓的CSM临床相关动物模型的背景下，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 并可能为诊断标记提供新的途径。通过MRI毫无侵袭检测异常的灌注 CSM患者随后的临床研究的明确翻译路径。该项目的调查人员团队 在所有不同主题领域都有个人专业知识，以及它们的综合多学科方法 这些研究将集体研究具有潜在高临床相关性和转化的新研究领域 机会。