Dynamics of the Traumatic Brain Injury Degradome.

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DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a complex neurological disease and a major burden in our society. TBI etiology requires many disciplines, including quantitative physical sciences, working together as outlined in the NIH roadmap. This Award fosters integration of quantitative scientists into focused study of TBI, which is the spirit of this proposal. As an analytical chemist, with expertise in quantitative mass spectrometry, I developed ground support instrumentation for the future safety of NASA Space Shuttle launches. More recently, I began to use quantitative mass spectrometry in protein studies, which is when I discovered the significant impact that my expertise would have on neurotrauma research. This Award will ensure my immediate career goal to transition into the health sciences via the following: 1) provide the funding and protected time necessary to receive training in neuroscience and molecular cell biology through course work, seminars and workshops; 2) provide written institutional commitments to support the above career development and a promotion to full-time tenure-track faculty in the College of Medicine; and 3) provide a structured mentored research environment within the renowned McKnight Brain Institute to develop biological research skills in the study of TBI, present and publish within the medical sciences, and generate preliminary data for future grant submissions as a primary investigator. Completing this proposal will position me to achieve my long-term goal of becoming a full-faculty independent investigator, combining quantitative and health science in the resolution of neurological disorders. The research proposed, combines the mentors' expertise in TBI and proteolysis in synergy with my quantitative chemistry background, and is the first large scale post-TBI degradomic study. This research will be conducted through the following four Specific Aims: 1) develop novel tagging chemistry methodology to identify in vitro brain substrates of TBI-relevant proteases; 2) define in vivo spatial and temporal dynamics of TBI-relevant protease activation after TBI; 3) characterize in vivo substrate degradation after TBI by quantifying substrates identified in Aim 1 within temporal and spatial profiles of protease activation revealed in Aim 2; and 4) assemble and publicly distribute a profile (map and timeline) of the TBI degradome. This research will provide a detailed characterization of molecular events that exacerbate brain damage after head trauma. An understanding of these events will foster development of novel diagnostics and therapeutics to reduce the burden of brain trauma on society.