Meningeal lymphatic dysfunction in traumatic brain injury: roles in disease pathogenesis andlong-term outcomes.

创伤性脑损伤中的脑膜淋巴功能障碍：在疾病发病机制和长期结果中的作用。

• 批准号: 10295031
• 负责人: Ashley C Bolte
• 金额: $ 5.1万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295031
• 关键词: Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid beta-Protein; Anatomy; Antigens; Anxiety; Automobile Driving; Behavioral; Biological Factors; Brain; Brain Injuries; Cause of Death; Cells; Chronic; Clinical; Cognitive deficits; Defect; Dementia; Development; Disease; Disease Outcome; Disease Progression; Drainage procedure; Event; Goals; Growth; Imaging Techniques; Immune response; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Learning; Lesion; Light; Link; Lymphatic; Lymphatic System; Lymphatic function; Measures; Mediating; Mediator of activation protein; Medical; Memory; Meningeal lymphatic system; Meninges; Mental Depression; Molecular; Motor Skills; Mus; Neuraxis; Neurodegenerative Disorders; Neurologic; Neurologic Dysfunctions; Operative Surgical Procedures; Organ; Outcome; Pathogenesis; Pathology; Pathway interactions; Pattern; Peripheral; Pharmaceutical Preparations; Population; Production; Recovery; Risk; Role; Series; System; Techniques; Therapeutic; Transgenic Mice; Traumatic Brain Injury; Vascular Endothelial Growth Factor C; Viral; Work; abeta accumulation; abeta deposition; aged; base; behavior test; behavioral outcome; behavioral response; chronic traumatic encephalopathy; cytokine; disability; experimental study; functional outcomes; glial activation; high risk; immune activation; improved; improved outcome; insight; lymphatic drainage; lymphatic dysfunction; mouse model; nervous system disorder; neuroinflammation; novel; overexpression; premature; protein aggregation

Project Summary/Abstract Traumatic brain injury (TBI) has emerged as a leading cause of death and disability. It results in a heightened risk for long-term disease sequelae including Alzheimer’s disease (AD) and chronic traumatic encephalopathy. Despite being a growing medical issue, the biological factors that promote central nervous system (CNS) pathology and neurological dysfunction following TBI remain poorly characterized. Recently, the CNS lymphatic system was identified as a critical mediator of drainage from the CNS to the periphery. In comparison to other peripheral organs, our understanding of how defects in lymphatic drainage from the CNS contribute to disease is limited. It is still unknown how TBI impacts CNS lymphatic function and whether disruptions in this drainage pathway are involved in driving TBI pathogenesis. In preliminary studies, I found that even mild forms of brain trauma cause severe deficits in CNS lymphatic drainage that can last out to at least two weeks post- injury. Moreover, I observed that pre-existing CNS lymphatic dysfunction mediated by targeted photoablation before TBI leads to increased neuroinflammation and cognitive deficits. Given these preliminary findings, I hypothesize that CNS lymphatic dysfunction contributes to TBI pathogenesis by promoting sustained inflammation in the brain and that impairments in this lymphatic system contribute to amyloid beta (Aβ) build-up in mouse models of AD. In Aim 1, I will use surgical, behavioral and imaging techniques to determine whether pre-existing lymphatic dysfunction contributes to increased inflammation in the brain and adverse long-term behavioral outcomes. In Aim 2, I will utilize lymphatic modulating techniques in a mouse model of AD to assess whether CNS lymphatic dysfunction after TBI results in buildup of Aβ in both the brain and meninges and whether boosting lymphatic function is able to decrease Aβ deposition in the brain. Collectively, this proposal will provide new insights into the consequences of CNS lymphatic dysfunction in TBI, shed light on the mechanisms behind why TBI results in a higher risk for neurodegenerative disease, and offer potential therapeutic options to target the CNS lymphatic system after TBI.

项目总结/摘要 创伤性脑损伤（TBI）已成为死亡和残疾的主要原因。这会导致 出现长期疾病后遗症的风险，包括阿尔茨海默病（AD）和慢性创伤性脑病。 尽管是一个日益增长的医学问题，生物因素，促进中枢神经系统（CNS） 创伤性脑损伤后的病理学和神经功能障碍的特征仍然很差。最近，中枢神经系统淋巴 系统被确定为从CNS向外周引流的关键介质。相较于其他 外周器官，我们对中枢神经系统淋巴引流缺陷如何导致疾病的理解 是有限的。目前尚不清楚TBI如何影响CNS淋巴功能，以及这种引流是否受到破坏。 信号通路参与驱动TBI发病机制。在初步研究中，我发现即使是轻微的大脑 创伤引起CNS淋巴引流严重缺陷， 损伤此外，我观察到靶向光消融介导的既存CNS淋巴功能障碍 在创伤性脑损伤导致神经炎症和认知缺陷之前根据这些初步调查结果，我 假设CNS淋巴功能障碍通过促进持续的TBI发病机制， 大脑中的炎症和淋巴系统的损伤有助于淀粉样蛋白β（A β）的积累 在AD的小鼠模型中。在目标1中，我将使用手术、行为和成像技术来确定 预先存在的淋巴功能障碍导致大脑炎症增加， 行为结果在目标2中，我将在AD小鼠模型中利用淋巴调节技术来评估 TBI后CNS淋巴功能障碍是否会导致A β在脑和脑膜中的积聚， 增强淋巴功能能够减少A β在大脑中的沉积。总的来说，这项提案将提供 对TBI中CNS淋巴功能障碍后果的新见解，揭示了TBI背后的机制。 为什么TBI导致神经退行性疾病的风险更高，并提供潜在的治疗选择， TBI后的CNS淋巴系统。