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.
Mild juvenile traumatic brain injury (jmTBI) is a major public health issue that is associated with a risk factor for cognitive decline and dementia. Therefore, it is critical to have a better understanding of the long-term changes in order to accurately develop new treatments to prevent these long-term cognitive sequelae. This proposal will test the hypothesis that in the context of vascular dysfunction and extracellular matrix (ECM) degradation that occurs in white matter (WM) after jmTBI, the neuroprotective and angiogenic C-terminal protein fragment domain V (DV) of the vascular ECM heparan sulfate proteoglycan perlecan, is acutely generated and plays a significant, potentially beneficial role to WM?s response to- and long-term cognitive consequences of jmTBI that could be therapeutically exploited.
