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

描述(申请人提供)：脑室扩大的发展是反复轻度创伤性脑损伤(RmTBI)的标志。然而，导致脑室扩张的机制、扩张的渐进性以及对重要的室间膜运输和清除机制的后果尚不清楚。研究旨在探讨在rmTBI中大脑所经历的加减速和旋转力如何导致脑室扩大，影响脑室衬里的完整性，并导致关键的脑室功能丧失。使用rmTBI的小鼠模型，初步研究显示撞击后一个月有大量的脑室表面胶质化和脑室扩大，在其他研究中，在没有任何神经元退化的情况下，脑室表面胶质化和脑室扩大之间已经建立了很强的相关性。为了验证这样一种假设，即rmTBI的反复冲击转化为沿脑室衬里的剪切力，导致撕裂、表面胶质化和脑室扩大，并随着时间的推移而进展，将确定表面胶质化和开始扩张的时间线。脑室表面细胞组织和相互作用的详细免疫组织化学特征，以及细胞分裂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。脑室体积将在3D中建模，局部表面疤痕/水肿区将被映射到扩张区域。为了验证室管膜细胞覆盖面积的丧失对室管膜衬里提供的屏障和过滤系统的显著损害的假设，将根据表面胶质增生的程度来评估整个室壁准备中的层流的延时成像，并评估室管膜和脑室周围区域的蛋白质聚集。此外，还将使用荧光示踪剂来评估跨室室膜转运的变化，并将调查脑室表面胶质化对脑室周围结构的影响。总之，建议的研究解决了跨室间膜转运和清除功能的丧失可能有助于rmTBI的一些脑部病理。重要的是，脑室扩大和相关的脑室周围水肿可以通过液体衰减反转恢复(FLAIR)MRI跟踪一段时间，强调如何使用标准诊断工具来评估脑室系统健康状况的进行性下降并告知后果。

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.