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。是 其特征在于脊髓的物理压迫并且通常在数月至数年内逐渐进展， 表现为虚弱麻木和疼痛因为它是一种不成比例地影响衰老的疾病 人口和导致生活质量下降，它有很高的相关性退伍军人。许多CSM患者 手术干预后有良好的结局，但通过机械干预改善结局的机会 了解疾病的过程和改进的诊断标志物将有助于提高诊断 和患者管理，可能导致治疗的改进。本项目旨在研究 在临床前动物模型中CSM背景下的扩散去极化和灌注缺陷。传播 去极化（SD）是一种通过中枢神经系统传播的异常的离子和电的波动 侮辱后的纸巾。虽然SD在急性身体创伤后已经得到了很好的建立和表征， 他们还没有被调查与持续或重复的物理压迫的脊髓，这是 CSM的标志。此外，SD和潜在的灌注缺陷是紧密耦合的。神经元有足够 氧气和葡萄糖可以从SD中恢复，但缺乏足够代谢底物的神经元具有高代谢底物， 可能会被SD造成不可修复的损坏。该项目将使用动物模型和电生理 记录以在连续或动态物理环境中表征脊髓中的SD事件， 压缩（目标1）。同时，它将使用MRI或椎管内检查脊髓中的灌注缺陷。 压力传感器在临床相关脊髓型颈椎病动物模型中的应用 压缩（目标2）。这些研究将有助于阐明脊髓型颈椎病的脊髓损伤机制 并可能为诊断标记物提供新的途径。用MRI无创检测异常灌注， 为CSM患者的后续临床研究提供了明确的转化途径。这个项目的调查小组 在所有不同的学科领域都有自己的专业知识，他们结合了多学科的方法， 这些研究将共同探讨一个新的研究领域，具有潜在的高临床相关性和转化 机会