This grant application seeks continued funding for the Head Injury Research Center at the University of Pennsylvania, a Center now in its 23rd year of existence. During that time, the research has become focused on TRAUMATIC AXONAL DAMAGE (TAD), an important focus of dysfunction in human brain injury, and, thus, TAD is the overall theme of the Center. TAD occurs in various forms in well over half of all fatal injuries examined pathologically and in a pure form, as diffuse axonal injury (DAI), in one-third of severely brain injured humans. To understand the pathophysiology of TAD better, this application proposes the use of state-of-the-art neuroimaging, spectroscopy, electron microscopy, immunohistochemical and molecular biologic methods in a coordinated research effort involving five projects. The first two projects utilize magnetic resonance transfer imaging (MTI) and spectroscopy (MRS) to determine non-invasively longitudinal changes in structure and in-vivo biochemistry of traumatic white matter abnormalities in experimental DAI and humans, respectively, and will combine these into methods to diagnose TAD clinically. A third project characterizes changes in expression of immediate early genes (IEG), stress proteins, target genes of the IEGs and neurotransmitters in models of TAD in order to determine the influence of genomic changes on responses to injury. A fourth project uses experimental models of TAD to determine efficacy of novel neuroprotective compounds targeted at receptor or cytoskeletal dysfunction in mitigating TAD. Two essential core activities support the Projects. Core A provides administrative activities, biostatistical support, patient database maintenance and evaluation of new outcome tools. Core B provides bioengineering support, designs improved models with higher fidelity in replicating human brain injury, and quantifies the relationships between experimental models and human injuries. Theses studies will further our understanding of the pathophysiology of brain injury and will lead to the development of novel and improved therapies for the treatment of brain injured patients.