权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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。

基本信息

批准号：
10468999
负责人：
Ashley C Bolte
金额：
$ 4.52万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468999
关键词：
Adult Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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 brain dysfunction chronic traumatic encephalopathy cytokine disability experimental study functional outcomes glial activation high risk immune activation improved improved outcome insight long-term sequelae lymphatic drainage lymphatic dysfunction mouse model nervous system disorder neuroinflammation novel overexpression premature protein aggregation

项目摘要

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/文摘