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

• 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
• 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

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.

经历创伤性脑损伤的退伍军人通常表现出深度和虚弱的睡眠，在他们的 脑电波活动和脑血管功能失调。睡眠紊乱会损害情绪，有能力 工作、认知、人际关系和整体生活质量。创伤性脑损伤导致局部脑损伤 脑部导致长期炎症增加和脑血流受损。有证据表明， 创伤性脑损伤会增加大脑中的氧化应激--这是一个已知的引发炎症的过程 脑细胞中的分子，如神经胶质细胞和神经元，可以改变脑血管功能。有趣的是，不断增长 有证据表明，炎症会影响脑血管功能，而血管功能会在 睡眠，尽管造成这些影响的确切机制还不是很清楚。这样做的目的是 建议是确定创伤性脑损伤如何诱导主要的睡眠调节性炎症途径 在睡眠、脑波活动和脑血管功能失调时受到氧化应激的影响。我们 假设创伤性脑损伤导致氧化应激导致慢性脑部炎症损害 脑血管功能损害睡眠和脑电波活动。我们使用分子和细胞技术， 多导睡眠图，以及动物模型中的血管测量，以达到本项目的目的。目标1决定 氧化应激诱导的主要睡眠调节性炎症通路的成分是什么 由创伤性脑损伤引起的脑内激活，导致睡眠、脑波活动和血管紊乱 功能。目的2研究创伤性脑是如何激活这一主要的睡眠调节炎症通路的 损伤导致局部和局部脑血管功能和脑波活动的变化 睡吧。从该项目获得的数据将提供关键信息，以了解 炎症和脑血管功能对创伤性脑损伤引起的睡眠和脑波活动的影响。 因此，这个项目的发现将提供与睡眠失调有关的新靶点的信息 这将导致未来为患有创伤性脑损伤的退伍军人开发新的治疗方法。