Perlecan therapy for white matter and cognitive impairment in closed head injury with long-term dysfunction (CHILD)

项目总结/摘要 青少年创伤性脑损伤，即使是最常见的轻度形式（青少年轻度TBI， jmTBI）是一个重大的公共卫生问题，与显著的长期发病率相关，是一个危险因素 认知能力下降到目前为止，对第一周的病理过程知之甚少。 jmTBI及其作为血管对认知障碍和痴呆的长期贡献的潜力 （VCID）。更好地了解长期变化，以便准确地开发新的 治疗以减少或预防VCID。我们以前证明了在大脑中的长期灰质变化， 神经血管单位（NVU）、血脑屏障（BBB）和脑细胞外基质蛋白的表达 中度/重度青少年TBI。然而，由于长期的白色物质（WM）变化也会发生， 在临床和临床前研究中，我们推测， 伴随细胞外基质（ECM）蛋白降解的jmTBI血管功能障碍显著有助于 长期WM损伤和VCID。有趣的是，在WM损伤和VCID的各种模型中， 血管ECM硫酸乙酰肝素蛋白聚糖、串珠素及其受体的WM表达增加， 神经保护和血管生成C-末端蛋白片段结构域V（DV）。我们假设 在血管功能障碍和ECM降解的背景下，DV在jmTBI后的WM中急性产生， 对WM对以下认知后果的反应和长期认知后果起着重要的、潜在的有益作用： jmTBI可以用于治疗。为了研究这一假设，我们开发了一种新的 小鼠jmTBI模型的闭合性头部损伤与长期功能障碍（命名为CHILD）， WM血管改变作为VCID模型。具体来说，我们建议确定细胞外的作用， 基质蛋白串珠素DV在WM神经血管单位的变化和jmTBI后长期认知功能下降中的作用 模型的VCID，并确定治疗潜力和内皮细胞的作用机制， 在jmTBI中的重组结构域V作为VCID的模型。

PROJECT SUMMARY / ABSTRACT Juvenile traumatic brain injury, even when in the most commonly occurring mild form (juvenile mild TBI, jmTBI), is a major public health issue that is associated with significant long-term morbidity and is a risk factor for cognitive decline. To date, very little is known about the pathological processes during the first week after jmTBI as well as their long-term potential as vascular contributions to cognitive impairment and dementia (VCID). It is critical to have a better understanding of the long-term changes in order to accurately develop new treatments to minimize or prevent VCID. We previously demonstrated long-term grey matter changes in the neurovascular unit (NVU), blood-brain barrier (BBB) and brain extracellular matrix proteins in experimental moderate/severe juvenile-TBI. However, as long-term white matter (WM) changes also occur and have been implicated in accelerated cognitive decline in clinical and pre-clinical studies, we hypothesize that early post- jmTBI vascular dysfunction with degradation of extracellular matrix (ECM) proteins significantly contributes to long-term WM injury and VCID. Intriguingly, in various models of WM injury and VCID, a significant acute increase in WM expression of the vascular ECM heparan sulfate proteoglycan, perlecan, as well as its neuroprotective and angiogenic C-terminal protein fragment domain V (DV), is observed. We hypothesize that in the context of vascular dysfunction and ECM degradation, DV is acutely generated in WM after jmTBI and plays a significant, potentially beneficial role to WM's response to- and long-term cognitive consequences of jmTBI that could be therapeutically exploited. To investigate this hypothesis, we have developed a novel mouse jmTBI model of Closed Head Injury with Long- term Dysfunctions (named CHILD) to investigate early WM vascular changes as a model of VCID. Specifically, we propose to determine the role of the extracellular matrix protein perlecan DV in WM neurovascular unit changes and long-term cognitive decline after jmTBI as a model of VCID, and to determine the therapeutic potential and endothelial cell mechanism of action of recombinant domain V in jmTBI as a model of VCID.