Inflammasome activation and lymphatic dysfunction in traumatic brain injury

创伤性脑损伤中的炎症小体激活和淋巴功能障碍

• 批准号: 10459460
• 负责人: John R Lukens
• 金额: $ 35.33万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459460
• 关键词: Affect; Aging; American; Architecture; Biological; Biological Factors; Brain; Brain Diseases; Brain Injuries; Cause of Death; Cell Death; Cells; Central Nervous System Diseases; Clinical; Complex; Craniocerebral Trauma; Defect; Deterioration; Disease; Disease Outcome; Disease Progression; Drainage procedure; Elderly; Excision; Foundations; Functional disorder; Health; Health system; Homeostasis; Impairment; Individual; Inflammasome; Inflammation; Inflammatory; Injury; Interleukin-1; Interleukin-18; Link; Lymphatic; Lymphatic System; Lymphatic function; Mediating; Medical; Meningeal lymphatic system; Meninges; Mus; Necrosis; Neuraxis; Neurologic; Neurologic Dysfunctions; Organ; Outcome; Pathogenesis; Pathology; Peripheral; Persons; Population; Production; Recovery; Rejuvenation; Reporting; Research; Role; Series; Severities; Signal Transduction; Stress; Structure; Techniques; Testing; Therapeutic; Time; Tissues; Traumatic Brain Injury; Work; World Health Organization; aged; aging brain; cell injury; disability; feasibility testing; innovation; lymphatic drainage; lymphatic dysfunction; lymphatic vessel; macromolecule; mild traumatic brain injury; nervous system disorder; neuroinflammation; neuropathology; novel; protein aggregation; response; tool

ABSTRACT Traumatic brain injury (TBI) affects millions of people worldwide every year and current estimates from the World Health Organization suggest that TBI will be the third leading cause of death and disability by the year 2020. Despite being a prevalent and pressing global medical issue, our understanding of TBI pathoetiology remains incomplete. Proper drainage of cellular debris by the lymphatic system is required to maintain tissue homeostasis and impaired removal of damage/stress signals, including damaged cells and protein aggregates, from organs has been linked to a spectrum of diseases. In comparison to other peripheral organs, our understanding of how our how defects in lymphatic drainage from the central nervous system (CNS) contribute to disease remains poorly described. In this project, we will investigate the consequences of compromised meningeal lymphatic function in TBI pathogenesis. In our preliminary studies, we found that TBI results in severely compromised brain lymphatic drainage and that pre-existing deficits in meningeal lymphatic function predisposes the brain to exacerbated clinical disease following brain trauma. To determine if the impaired clearance of endogenous damage/stress signals (e.g., cellular debris and necrotic cells) was associated with inflammatory signaling, we evaluated inflammasome complex formation in TBI. Inflammasomes are multiprotein oligomeric platforms that coordinate IL-1 and IL-18 production, as well as an inflammatory form of cell death in response to damage/stress signals. We find that injury-induced meningeal lymphatic dysfunction is associated with pronounced inflammasome formation and accumulation in the TBI brain. Moreover, our preliminary findings and work from others demonstrate critical roles for inflammasome activation in TBI disease pathogenesis. Given these collective findings, we hypothesize that aberrant inflammasome signaling that results from meningeal lymphatic dysfunction mechanistically contributes to TBI pathogenesis. To test this, we propose three aims. In Aim 1, we will employ a series of cutting-edge meningeal lymphatic modifying approaches to identify how modulation of brain drainage influences TBI disease progression. In Aim 2, will determine to what extent inflammasome signaling downstream of meningeal lymphatic dysfunction mechanistically contributes to TBI pathology. In the third Aim, we will investigate how CNS lymphatic decline that occurs with aging influences TBI disease outcomes in the elderly. This research is innovative because it will break new ground in our understanding of how disruptions in brain drainage and the resulting buildup of inflammasome oligomers influence CNS disease progression. Moreover, our preliminary studies suggest that modulation of the meningeal lymphatics and inflammasome signaling can potentially serve as much-needed therapeutic strategies to treat TBI, which further underscores the translational value of these studies.

摘要 创伤性脑损伤（TBI）每年影响全世界数百万人， 世界卫生组织预测，到2020年，TBI将成为导致死亡和残疾的第三大原因。 2020.尽管是一个普遍和紧迫的全球医学问题，我们对TBI病因的理解 仍然不完整。淋巴系统需要适当地排出细胞碎片以维持组织 稳态和受损的损伤/应激信号的去除，包括受损的细胞和蛋白质聚集体， 与一系列疾病有关与其他外周器官相比， 了解我们如何从中枢神经系统（CNS）淋巴引流的缺陷， 对疾病的描述仍然很少。在这个项目中，我们将调查妥协的后果。 脑膜淋巴功能在TBI发病机制中的作用在我们的初步研究中，我们发现TBI会导致 严重损害脑淋巴引流和脑膜淋巴功能的预先存在的缺陷 在脑外伤后使脑易于恶化临床疾病。以确定是否受损 内源性损伤/应激信号的清除（例如，细胞碎片和坏死细胞）与 为了研究炎症信号，我们评估了TBI中炎性体复合物的形成。炎性小体是 协调IL-1和IL-18产生的多蛋白寡聚平台，以及炎性形式的 响应损伤/应激信号的细胞死亡。我们发现损伤引起的脑膜淋巴功能障碍 与TBI脑中显著的炎性小体形成和积聚有关。而且我们 初步的发现和其他人的工作证明了炎性小体激活在TBI疾病中的关键作用 发病机制鉴于这些共同的发现，我们假设， 脑膜淋巴功能障碍的结果在机械上有助于TBI发病机制。为了验证这个，我们 提出三个目标。在目标1中，我们将采用一系列尖端的脑膜淋巴修饰技术， 确定脑引流的调节如何影响TBI疾病进展的方法。在目标2中，将 确定脑膜淋巴功能障碍下游炎性小体信号传导的程度 机械地有助于TBI病理学。在第三个目标中，我们将研究中枢神经系统淋巴功能下降是如何发生的。 随着年龄的增长而发生的变化影响老年人TBI疾病的结局。这项研究是创新的，因为它 将为我们理解大脑排水中断以及由此产生的 炎性小体寡聚体影响CNS疾病进展。此外，我们的初步研究表明， 脑膜炎和炎性体信号传导的调节可以潜在地作为急需的 治疗TBI的治疗策略，这进一步强调了这些研究的转化价值。