Dynamics of the Traumatic Brain Injury Degradome.

描述（申请人提供）：创伤性脑损伤（TBI）是一种复杂的神经系统疾病，是我们社会的主要负担。TBI病因学需要许多学科，包括定量物理科学，如NIH路线图所概述的那样共同努力。该奖项旨在促进定量科学家对TBI的集中研究，这也是本提案的精神所在。作为一名分析化学家，在定量质谱方面拥有专业知识，我为美国宇航局航天飞机发射的未来安全开发了地面支持仪器。最近，我开始在蛋白质研究中使用定量质谱法，那时我发现我的专业知识将对神经创伤研究产生重大影响。该奖项将确保我的近期职业目标，通过以下方式过渡到健康科学：1)通过课程、研讨会和讲习班提供必要的资金和保护时间，以接受神经科学和分子细胞生物学方面的培训；2)提供书面的机构承诺，以支持上述职业发展，并晋升为医学院的全职终身教师；3)在著名的麦克奈特脑研究所（McKnight Brain Institute）提供结构化的指导研究环境，以培养TBI研究中的生物研究技能，在医学科学领域发表和发表，并作为主要研究者为未来的拨款申请提供初步数据。完成这项提案将使我实现成为一名全职独立研究者的长期目标，将定量和健康科学结合起来解决神经系统疾病。该研究将导师在脑损伤和蛋白水解方面的专业知识与我的定量化学背景相结合，是脑损伤后第一个大规模的降解研究。本研究将通过以下四个具体目标进行：1)开发新的标记化学方法来鉴定脑外伤相关蛋白酶的体外脑底物；2)明确脑外伤后脑外伤相关蛋白酶激活的体内时空动态；3)通过量化Aim 1中鉴定的底物，在Aim 2中揭示的蛋白酶激活的时空分布中表征TBI后体内底物降解；4)收集并公开发布TBI退化概况（地图和时间轴）。这项研究将提供一个详细的表征分子事件，加剧脑损伤后的头部创伤。对这些事件的了解将促进新的诊断和治疗方法的发展，以减轻脑外伤对社会的负担。

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.