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

项目摘要/摘要 创伤性脑损伤已成为人类死亡和致残的主要原因。它导致了一个高度的 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。 尽管这是一个日益严重的医学问题，但促进中枢神经系统(CNS)的生物因素 颅脑损伤后的病理和神经功能障碍仍缺乏特征性。最近，中枢神经系统淋巴管 系统被认为是中枢神经系统向外周引流的关键媒介。与其他人相比 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。目前尚不清楚创伤性脑损伤如何影响中枢淋巴功能，以及引流是否中断 这些通路参与了脑外伤的发病机制。在初步研究中，我发现即使是轻微形式的大脑 创伤导致中枢神经系统淋巴引流严重不足，至少可持续两周后- 受伤。此外，我观察到，通过靶向激光消融，先前存在的中枢神经系统淋巴功能障碍 在创伤性脑损伤导致神经炎症和认知障碍增加之前。鉴于这些初步调查结果，我 中枢淋巴系统功能障碍通过促进持续性脑损伤发病机制的假说 大脑中的炎症和淋巴系统的损伤导致淀粉样β蛋白(Aβ)的积聚 在阿尔茨海默病小鼠模型中。在目标1中，我将使用外科手术、行为和成像技术来确定 预先存在的淋巴功能障碍会增加大脑中的炎症，并对长期不利 行为结果。在目标2中，我将利用淋巴调节技术在阿尔茨海默病小鼠模型中评估 颅脑损伤后中枢淋巴系统功能障碍是否导致脑和脑膜中Aβ的积聚 增强淋巴功能能够减少Aβ在大脑中的沉积。总体而言，这项提案将提供 对脑外伤后中枢神经系统淋巴功能障碍后果的新见解，揭示了背后的机制 为什么脑外伤导致神经退行性疾病的风险更高，并为靶向提供潜在的治疗选择 颅脑损伤后中枢淋巴系统的变化。

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.