Traumatic brain and spinal cord injuries often result in permanent disabilities that can profoundly affect the quality of life. The extent of functional recovery after either traumatic brain or spinal cord injury is a consequence of the initial mechanical destruction of tissue and of secondary factors that collectively contribute to additional tissue damage. The challenge is to carefully define these factors, determine the time course of their expression, and to develop therapeutic interventions that target their temporal “window” of expression. To address these complex objectives, we have developed and characterized reproducible models of traumatic brain and spinal cord injury in the rodent that accurately mimic the human condition. These models have been used to recently study the role of matrix metalloproteinases in both the acutely and chronically injured spinal cord and to address the unique vulnerability of the immature brain to traumatic brain injury.
Current Research Projects
Spinal cord injury
We have shown that matrix metalloproteinases (MMPs), a family of zinc and calcium requiring endopeptidases, play differing roles in the acutely injured spinal cord and during wound healing. Strategies to reduce MMP activity and in particular MMP-9 in the acutely injured cord result in stabilization of the blood-spinal cord barrier, reduced leukocyte infiltration, and impaired motor recovery. However, recent studies show that these beneficial effects are lost if MMP blockade is extended beyond the first 3 days post injury into the period of wound healing. The contributions of MMPs to acute injury responses and wound healing events are dependent upon which MMPs are expressed, when they are expressed, where they are expressed, and how much is being expressed. Our studies, which have focused on the gelatinases (MMP-9 and MMP-2), illustrate these points. MMP-9 activity is limited to the acutely injured spinal cord, whereas MMP-2 activity peaks during wound healing. Studies, using MMP-9 and MMP-2 null mice, have shown one (MMP-9) to mediate tissue injury and limit motor recovery while the other (MMP-2) modulates glial scar formation. Ongoing studies, using both pharmacologic and genetic approaches are intended to more closely examine how these MMPs interact in the injured spinal cord. We are particularly interested in their contributions to leukocyte trafficking, angiogenesis, and remodeling of the extracellular matrix. More ►
Although there has been substantial research to understand the neurobiologic basis for persistent impaired cognitive and motor deficits after traumatic brain injury in the adult, less attention has been directed toward the brain-injured child. Clinical data suggest that children less than 4 years of age exhibit more cognitive deficits as they mature, than older children. One explanation for this increased vulnerability may be related to the timing of the injury, which occurs during the critical period of development. We have developed and characterized a model of traumatic brain injury in the young mouse that results in both cortical and subcortical neuronal injury and an overt cognitive deficit. Two significant findings have resulted from these recent studies. First, there is clear evidence that vulnerability is related to the reduced antioxidant capacity of the developing brain. Second, neuronal loss is not limited to the acutely injured brain but rather extends over a period of time during brain maturation. Importantly, cognitive deficits are delayed in onset. They are not apparent by 2 weeks post injury but rather coincide with brain maturation. These exciting findings suggest that there may be an extended therapeutic window of time to treat the brain-injured child. Our current studies focus on early inflammation and antioxidant reserves as determinants of structural and cognitive recovery after brain injury. More ►