Traumatic brain injury (TBI) results in long term debilitation for millions of Americans. A consistent feature of this pathology is traumatic axonal injury (TAI), diffuse in profile and challenging to study. To date, TAI etiology is best documented in large caliber, myelinated axons, which consistently exhibit plasmalemmal, cytoskeletal and mitochondria! pathology. From diagnostic imaging it is clear that the corpus callosum and other subcortical white matter tracts are vulnerable to TAI. These pathways contain both large myelinated and small unmyelinated axons, where fiber type is systematically associated with sensorimotor and associative cortices. Given that TBI induces long-term cognitive deficits, and that TAI in subcortical white matter is poorly understood, our recently published studies have explored the physiological and morphological response of corpus callosum axons to diffuse TBI. Those results show rapid evolution of TAI and greater vulnerability of unmyelinated fibers. In parallel, pilot studies we also find upregulation of extracellular matrix (ECM) proteins and their regulatory metalloproteinases (MMPs) with callosal TAI. Such observations are consistent with the fact that these proteins mediate axonal growth, myelination and fasciculation. Based upon this information, we propose to explore the role of MMP/ECM pathways during degenerative and recovery phases of TAI. We will test the hypothesis that MMP/ECM proteins influence the progression of white matter TAI following TBI and that their activation is regulated by fibrinolytic proteins which permeate the neuropil through breaches in the blood brain barrier. Using the callosal TAI model, we will document protein/mRNA expression of tenascin and phosphacan, ECM proteins known to be present in white matter, and MMPs 2, 3 and 9, known to modify ECM after injury. Temporal profile of MMP activity will be correlated with enzyme expression and screening for adhesion molecule binding partners of these proteins will be performed. Next, we will similarly assess the response of fibrinolytic pathway proteins tPA and plasminogen to callosal TAI. Finally, we will pharmacologically manipulate either fibrinolytic/MMP enzyme activity or degree of axonal protection after injury and test for cause/effect relationships between fibrinolytic/MMP molecules and axonal integrity using functional and morphological endpoints. These studies will establish the role of MMP/ECM proteins in TAI and provide new therapeutic targets forTBI.
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