PROJECT SUMMARY- ABSTRACT Currently, preclinical TBI research and testing of experimental therapeutic in animal models of TBI models, the most commonly used outcome endpoints are lesion volume/size, neuronal cell preservation and behavioral functional outcome measures (such as Morris water maze, rotarod). While these measures are clearly useful – they lack the ability to inform on the underlying distinct pathophysiological mechanisms relevant in human TBI. These factors might have contributed to the lack of translational success for new TBI therapeutics from animal models efficacy to clinical trial efficacy. Consistent with the vision of the Translational Outcomes Project in Neurotrauma (TOP- NT) (UG3/UH3) RFA, here we carefully assembled a multidisciplinary team and proposed to evaluate two complementary pathological mechanism-based TBI outcome measures – (i) biofluid biomarker assessment, and (ii) MRI-neuroimaging biomarker assessment. These assessments are chosen because they are both highly quantitative and can readily transition into clinical TBI studies and future therapeutic trials. Our central hypothesis is as follows: In preclinical multi-site multi-TBI animal model setting, biofluid-based biomarker and quantitative MRI-based neuroimaging biomarker assessment can be developed into useful translational outcome measures that can help address a range of clinical TBI pathological mechanistic subphenotypes including axonal injury, contusion/tissue necrosis, loss of synaptic continuity, white matter injury, microvascular injury/brain hemorrhage and neuroinflammation. We have also put together a “Clinical TBI Translational Advisory” panel to assist us with translating our findings into clinical studies.