Although multiple lines of experimental evidence implicate calpains in the process of secondary neurodegeneration following traumatic brain injury (TBI), little is understood about the downstream actions of calpains in the injured brain, and how these pathways might differ in focal and diffuse TBI. In addition to elucidating novel targets and cellular pathways for calpains in the injured brain, the Program will evaluate several novel strategies to inhibit posttraumatic calpain activation, including enhancing activity of calpastatin, knocking out the calpain I isoform, and administering small molecule inhibitors. The overall goal of the Animal Core (Core B) is to facilitate the Program's investigations of calpain-mediated neuropathology and evaluations of calpain inhibitory therapeutic strategies in mouse models of focal and diffuse TBI. To thisend, the Core will perform three specific functions in support of Program objectives: 1) produce consistent, predictable focal or diffuse traumatic brain injuries in mice to be further evaluated in Projects 1, 2, and 3 and in Core C, 2) provide reliable, unbiased assessments of posttraumatic cognitive and motor function in brain- injured and control mice for evaluation of strategies to reduce posttraumatic calpain activation pursued in Projects 1, 2 and 3, and 3) maintain and expand, as necessary, colonies of human calpastatin overexpressing mice, calpastatin deficient mice, calpain I knockout mice and cyclophilin D deficient mice for use in Projects 1 and 3 and Core C. Through these three major functions, the Animal Core will increase the efficiency of the Program by reducing redundancy in training, personnel and resources, and will enhance the ability of Projects and Cores to directly compare data by minimizing variability. In addition, the Core will provide behavioral assessments under blinded conditions and will provide centralized management of transgenic and knockout mouse resources vital to the Program's scientific interests. The activities of the Core are essential to the successful completion of the scientific goals of the Program.
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