Inflammation, Neurovascular Hemodynamics, and Sleep in Traumatic Brain Injury

创伤性脑损伤中的炎症、神经血管血流动力学和睡眠

基本信息

批准号：
10361592
负责人：
Mark Robert Zielinski
金额：
--
依托单位：
VA BOSTON HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10361592
关键词：
Affect Animal Model Area Arteries Astrocytes Binding Blood Vessels Brain Brain Injuries C57BL/6 Mouse Cell Separation Cerebrovascular Circulation Cerebrovascular system Cerebrum Chronic Clustered Regularly Interspaced Short Palindromic Repeats Cognition Complex Coupling Cre lox recombination system Data Development Devices Electroencephalogram Encephalitis Environment Enzyme-Linked Immunosorbent Assay Etiology Excessive Daytime Sleepiness Exhibits Family Flow Cytometry Frequencies Future Gene Expression Profiling Goals Health Healthcare Systems Hypothalamic structure Immunohistochemistry Impaired cognition Impairment Incidence Inflammasome Inflammation Inflammatory Interleukin-1 beta Laser-Doppler Flowmetry Leucine Literature Measurement Measures Microglia Microspheres Molecular Molecular Biology Molecular Target Moods Mus Myography Neuroglia Neurons Nucleotides Oxidative Stress Pathway interactions Personal Satisfaction Phase Physiological Polysomnography Process Property Quality of life Regulation Role Severities Site Sleep Sleep disturbances Sleeplessness Spectrophotometry TXNIP gene Techniques Thalamic structure Therapeutic Time Transgenic Mice Traumatic Brain Injury Travel United States United States Department of Veterans Affairs Vascular resistance Veterans Western Blotting Work adeno-associated viral vector brain cell brain dysfunction cognitive function comorbidity controlled cortical impact density design experience experimental study hemodynamics improved marenostrin mild traumatic brain injury neuroinflammation neurovascular new therapeutic target non rapid eye movement novel novel therapeutic intervention protein complex severe injury transcriptome sequencing

项目摘要

Veterans that experience traumatic brain injury often exhibit profound and debilitating sleep, impairments in their brain wave activity, and dysregulated brain vascular functions. Disturbed sleep can impair mood, the ability to work, cognition, relationships, and overall quality of life. Traumatic brain injury results in localized damage to the brain inducing long-term increased inflammation and impairments in cerebral blood flow. Evidence indicates that traumatic brain injury damage increases oxidative stress in the brain—a process known to induce inflammatory molecules in brain cells, such as glia and neurons, that alters brain vascular functions. Interestingly, growing evidence suggests that inflammation affects brain vascular functions and that vascular functions change during sleep, although the exact mechanism responsible for these effects are not well understood. The goal of this proposal is to determine how traumatic brain injury induces a major sleep regulatory inflammatory pathway affected by oxidative stress in dysregulating sleep, brain wave activity, and brain vascular functions. We hypothesize that traumatic brain injury drives oxidative stress to induce chronic brain inflammation impairing brain vascular functions to impair sleep and brain wave activity. We use molecular and cellular techniques, polysomnography, and vascular measurements in animal models for the aims of this project. Aim 1 determines how components of a major sleep regulatory inflammatory pathway that is induced by oxidative stress is activated in the brain by traumatic brain injury resulting in dysregulated sleep, brain wave activity and vascular functions. Aim 2 examines how this major sleep regulatory inflammatory pathway is activated by traumatic brain injury to induce both local and regional changes in brain vascular functioning and brain wave activity during sleep. Data obtained from this project will provide critical information to understand the relationship between inflammation and brain vascular functions on sleep and brain wave activity occurring from traumatic brain injury. Thus, the findings from this project will provide information about novel targets involved in sleep dysregulation which will lead to the future development of novel treatments for veterans with traumatic brain injury.

经历过脑外伤的退伍军人通常会表现出严重的睡眠障碍、精神障碍脑电波活动和脑血管功能失调会损害情绪和能力。创伤性脑损伤会导致工作、认知、人际关系和整体生活质量的局部损伤。有证据表明，长期的炎症增加和脑血流受损。创伤性脑损伤会增加大脑的氧化应激，这是一种已知会诱发炎症的过程脑细胞中的分子，例如神经胶质细胞和神经元，可以改变脑血管功能。有证据表明，炎症会影响脑血管功能，并且血管功能会在睡眠，尽管造成这些影响的确切机制尚不清楚。提议是确定创伤性脑损伤如何诱导主要的睡眠调节炎症途径受氧化应激影响，导致睡眠、脑电波活动和脑血管功能失调。其次，创伤性脑损伤会驱动氧化应激，诱发慢性脑炎症损害我们使用分子和细胞技术来损害脑血管功能，多导睡眠图和动物模型中的血管测量为本项目的目标 1 确定。由氧化应激诱导的主要睡眠调节炎症途径的组成部分是如何变化的因创伤性脑损伤而在大脑中被激活，导致睡眠、脑电波活动和血管失调目标 2 检查这一主要的睡眠调节炎症通路如何被创伤性大脑激活。损伤导致脑血管功能和脑电波活动的局部和区域变化从该项目获得的数据将为理解睡眠之间的关系提供关键信息。炎症和脑血管功能对睡眠和脑外伤引起的脑电波活动的影响。因此，该项目的研究结果将提供有关睡眠失调的新靶标的信息这将导致未来针对患有创伤性脑损伤的退伍军人开发新的治疗方法。