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

项目摘要/摘要

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.