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经常表现出深刻而令人沮丧的睡眠，他们的障碍 脑波活性和脑血管功能失调。睡眠不安会损害情绪，能力 工作，认知，人际关系和整体生活质量。创伤性脑损伤导致对局部损害 大脑诱导的长期感染和脑血流损伤。证据表明 创伤性脑损伤会增加大脑中的氧化物压力 - 这是已知引起炎症的过程 脑细胞中的分子，例如神经胶质和神经元，会改变脑血管功能。有趣的是，成长 有证据表明炎症会影响脑血管功能，并且血管功能在 睡眠，尽管造成这些影响的确切机制尚不清楚。目标的目标 提案是确定创伤性脑损伤如何引起主要的睡眠调节性炎症途径 在睡眠不足，脑波活动和脑血管功能的失调中受氧化应激的影响。我们 假设创伤性脑损伤会驱动氧化应激引起慢性脑感染损害 脑血管功能会损害睡眠和脑波活动。我们使用分子和细胞技术， 动物模型中的多摄影术和血管测量，以实现该项目的目的。 AIM 1确定 氧化应激引起的主要睡眠调节炎症途径的主要成分是如何的 通过创伤性脑损伤在大脑中激活，导致睡眠失调，脑波活性和血管 功能。 AIM 2检查如何通过创伤性大脑激活这种主要的睡眠调节性炎症途径 在脑血管功能和脑波活动中引起局部和区域变化的伤害 睡觉。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脑损伤创伤的睡眠和脑波活性。 这是这个项目的发现将提供有关睡眠失调涉及的新型目标的信息 这将导致对脑损伤的退伍军人的未来发展。