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Repeated Mild Traumatic Brain Injury and its Impact on Ventricle System Health

反复轻度创伤性脑损伤及其对心室系统健康的影响

基本信息

批准号：
8909227
负责人：
JOANNE C CONOVER
金额：
$ 22.8万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8909227
关键词：
Acceleration Address Adherens Junction Affect Age Animal Model Antibodies Apical Area Attenuated Axon Binding Blast Injuries Brain Brain Pathology Cell Communication Cell surface Cells Cerebral Ventricles Cerebrospinal Fluid Cicatrix Cilia Complex Computer software Corpus Callosum Corpus striatum structure Deceleration Defect Development Diagnosis Diagnostic Disease Edema Ependymal Cell Epithelial Cells Event Experimental Designs Failure Filtration Generations Gliosis Head Health Health system Homeostasis Image Immunohistochemistry Impairment Injury Intercellular Fluid Intraventricular Injections Label Lateral Liquid substance Magnetic Resonance Imaging Maps Methods Modeling Movement Mus Nature Nerve Degeneration Neuraminidase Neurofibrillary Tangles Neurons Pathology Permeability Pilot Projects Preparation Proteins Publishing Radioactive Tracers Recovery Role Rotation Sampling Scanning Septum Pellucidum Severities Sports Stem cells Stretching Structure Surface System Testing Time Toxin Tracer Translating Ventricular Function War astrogliosis base chronic traumatic encephalopathy experience extracellular lateral ventricle mild traumatic brain injury monolayer mouse model neuropsychiatry novel protein aggregation solute stem cell niche tau Proteins tau aggregation time use tool transmission process ventricular system

项目摘要

DESCRIPTION (provided by applicant): Development of enlarged cerebral ventricles is a hallmark of repeated mild traumatic brain injury (rmTBI). However, the mechanisms leading to ventricle expansion, the progressive nature of expansion and the consequence to important transependymal transport and clearance mechanisms are not understood. Studies are proposed to investigate how acceleration/deceleration and rotational force experienced by the brain in rmTBI results in ventricle enlargement, affects the integrity of the ventricle lining and leads to loss of critical ventricle functions. Using a mouse model of rmTBI, preliminary studies revealed substantial ventricle surface gliosis and ventricle enlargement one-month post-impact and in other studies, a strong correlation between surface gliosis and ventricle expansion in the absence of any neuronal degeneration has been established. To test the hypothesis that the repeated impacts from rmTBI is translated to shear force along the ventricle lining, resulting in tearing, surface gliosis and ventricle enlargement that progresses over time, a time line for surface gliosis and onset of expansion will be determined. Detailed immunohistochemical characterization of cell organization and interactions at the ventricle surface, and the contributions by dividing cells to glial scar formation will establish the sequence of events leading to scarring and expansion. Ventricle volumes will be modeled in 3D and regional surface scarring/edema will be mapped to areas of expansion. To test the hypothesis that loss of areas of ependymal cell coverage to gliosis significantly compromises the barrier and filtration system provided by the ependymal lining, time-lapsed imaging of laminar flow in whole-mount preparations of the ventricle wall will be evaluated based on extent of surface gliosis, and protein aggregation in ependymal and periventricular regions evaluated. In addition, fluorescent tracers will be used to evaluate changes in transependymal transport, and the impact ventricle surface gliosis has on periventricular structures will be investigated. Together, the proposed studies address how loss of transependymal transport and clearance functions may contribute to some of the brain pathology found in rmTBI. Importantly, ventricle enlargement and associated periventricular edema can be tracked over time by fluid attenuated inversion recovery (FLAIR) MRI highlighting how a standard diagnostic tool can be used to assess progressive decline of ventricle system health and inform about the consequences.

描述（由申请方提供）：脑室扩大的发展是反复轻度创伤性脑损伤（rmTBI）的标志。然而，导致心室扩张的机制、扩张的进行性以及重要的经室管膜转运和清除机制的后果尚不清楚。提出研究以调查rmTBI中大脑经历的加速/减速和旋转力如何导致心室扩大，影响心室衬里的完整性并导致关键心室功能的丧失。使用rmTBI的小鼠模型，初步研究揭示了撞击后一个月大量的心室表面神经胶质增生和心室扩大，并且在其他研究中，在没有任何神经元变性的情况下，已经建立了表面神经胶质增生和心室扩大之间的强相关性。为了检验以下假设：rmTBI的重复冲击转化为沿心室衬里的剪切力沿着，导致撕裂、表面神经胶质增生和心室扩大，并随时间推移而进展，将确定表面神经胶质增生和扩张开始的时间线。脑室表面细胞组织和相互作用的详细免疫组织化学表征，以及分裂细胞对胶质瘢痕形成的贡献，将建立导致瘢痕形成和扩张的事件序列。将在3D中对血管体积进行建模，并将局部表面瘢痕/水肿映射到扩张区域。为了检验室管膜细胞覆盖面积损失至胶质增生显著损害室管膜衬里提供的屏障和过滤系统的假设，将基于表面胶质增生的程度评价心室壁整体标本中层流的延时成像，并评价室管膜和室周区域中的蛋白质聚集。此外，将使用荧光示踪剂评价经室管膜转运的变化，并研究心室表面胶质增生对室周结构的影响。总之，拟议的研究解决了如何损失的经室管膜运输和清除功能可能有助于rmTBI中发现的一些脑病理学。重要的是，可以通过液体衰减反转恢复（FLAIR）MRI随时间跟踪心室扩大和相关的室周水肿，突出显示如何使用标准诊断工具来评估心室系统健康的进行性下降并告知后果。