Validation of Putative Serum of Axonal Damage After Mild TBI

描述(申请人提供)：研究目的：检测创伤性轴索损伤(AI)的可能蛋白质标记物，以阐明轻度创伤性脑损伤(轻度TBI)及其后遗症的神经病理学。职业发展目标：提供足够的时间指导新的临床研究人员，并在TBI中进行以患者为中心的研究。研究项目：轴突损伤被认为是轻度颅脑损伤后认知和运动障碍的病理生理过程。这一建议的中心假设是轴突损伤导致血清和脑脊液(CSF)蛋白质的差异表达，检测这些蛋白质可以深入了解轴突损伤的机制。该项目的目标是检查血液和脑脊液的变化，以检验与轻度脑外伤的生化和细胞反应相关的几个假说。这一目标将通过两个研究策略来实现：1)分析血清和脑脊液蛋白的暴露特征；以及2)轴突损伤的蛋白质标记物与弥散张量成像(DTI)上轴突结构的变化和认知功能的相关性。具体地说，该项目试图确定神经丝损伤标志物(PNFH)和脂质调节标志物(ApoA1)在轻度脑外伤后轴突损伤中的可能作用。通过对循环白细胞DNA的表观遗传学变化的分析，将探索轻度脑损伤与神经退行性变长期风险增加之间的潜在联系。为了解决这些目标，PIs建议召集一组参加接触性运动的大学运动员，其中轻度脑损伤是已知的风险，以及一组中到重度脑外伤患者，作为他们临床护理的一部分，他们放置了脑室外引流。由于本研究涉及轻、中、重型颅脑损伤后脑结构和功能的多个方面的研究，因此它是指导对创伤性脑损伤感兴趣的新的临床研究人员的理想平台。这项建议符合K24奖的目标，1)表明PI需要投入更多的时间来加强他的研究能力，2)提供理想的条件，在这种条件下，新的临床研究人员可以在以患者为导向的研究中得到指导。 公共卫生相关性：在美国，轻度脑外伤是一个重要的公共卫生问题，目前没有客观的诊断援助，也没有治疗方法。这种伤害每年影响超过120万美国人，是伊拉克和阿富汗冲突的标志性伤害。轻微的脑损伤会导致思考和日常活动的问题，可能会持续几个月到几年。脑细胞受损的过程以及这种损伤如何与大脑功能障碍联系在一起，目前还不完全清楚。这阻碍了可以改善伤者生活的治疗方法的开发。PI建议检查血液和脊髓液的变化，以了解更多关于轻度脑外伤的信息。在这一过程中，他们希望培训和激励对创伤性脑损伤感兴趣的新一代临床研究人员。

DESCRIPTION (provided by applicant): Research Goals: To examine putative protein markers of traumatic axonal injury (AI) in order to elucidate the neuropathology of mild traumatic brain injury (mild TBI) and its sequelae. Career Development Goals: To provide adequate time to mentor new clinical investigators and perform patient-oriented research in TBI. Research Project: Axonal injury is thought to be the pathophysiological process that underlies the cognitive and motor deficits found after mild TBI. The central hypothesis of this proposal is that axonal injury results in the differential expression of serum and cerebrospinal fluid (CSF) proteins and that examination of these proteins can provide insight into the mechanism of axonal injury. The goal of this project is to examine alterations in blood and CSF to test several hypotheses related to the biochemical and cellular response to mild TBI. This goal will be accomplished through two investigative strategies: 1) Analysis of the exposure characteristic of serum and CSF proteins; and 2) Correlation of protein markers of axonal damage to changes in axonal structure on diffusion tensor imaging (DTI) and cognitive function. Specifically, this project seeks to determine the putative role of a marker of neurofilament damage (pNFH) and a marker of lipid regulation (ApoA1) in axonal injury after mild TBI. The potential link between mild TBI and the increased long-term risk of neurodegeneration will be explored by an analysis of epigenetic changes in the DNA of circulating leukocytes. To address these aims the PIs propose to assemble a cohort of college athletes participating in contact sports in which mild TBI is a known risk, and a cohort of moderate to severe TBI patients who have an external ventriculostomy drain placed as a part of their clinical care. Because this study involves the investigation of several aspects of brain structure and function after mild, moderate and severe TBI, it serves as an ideal platform for the mentoring of new clinical investigators interested in traumatic brain injury. This proposal meets the goals of the K24 award by 1) demonstrating the need for the PI to devote more time to and to augment his research capabilities, and by 2) providing the ideal conditions under which new clinical investigators can be mentored in the conduct of Patient-Oriented Research. PUBLIC HEALTH RELEVANCE: Mild TBI is an important public health problem in the US for which there is currently no objective diagnostic aid and no treatment. This injury affects over 1.2 million Americans annually and is the signature injury of the conflicts in Iraq and Afghanistan. Mild TBI can result in problems of thinking and performing daily activities that can last from months to years. The process by which brain cells are damaged and how this damage is linked to brain dysfunction is incompletely understood. This has prevented the development of treatments that could improve the lives of those injured. The PIs propose to examine changes in the blood and spinal fluid to learn more about mild TBI. In the process they hope to train and inspire a new generation of clinical researchers interested in traumatic brain injury.