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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

基本信息

批准号：
9977266
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
项目类别：
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/9977266
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 Mediating Medical Meningeal Meninges Mus Necrosis Neuraxis Neurologic Neurologic Dysfunctions Organ Outcome Pathogenesis Pathology Peripheral 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 innovation lymphatic drainage lymphatic vessel macromolecule mild traumatic brain injury nervous system disorder neuroinflammation neuropathology novel protein aggregation response tool

项目摘要

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