Validation of Putative Serum of Axonal Damage After Mild TBI

描述（由申请人提供）：研究目标：检查创伤性轴突损伤（AI）的推定蛋白质标志物，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：提供足够的时间来指导新的临床研究者，并在TBI中进行以患者为导向的研究。研究项目：轴索损伤被认为是导致轻度脑外伤后认知和运动缺陷的病理生理过程。该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，并且检查这些蛋白质可以提供对轴突损伤机制的了解。该项目的目标是检查血液和CSF的变化，以测试与轻度TBI的生化和细胞反应相关的几个假设。这一目标将通过两种研究策略来实现：1）分析血清和CSF蛋白的暴露特征; 2）轴突损伤的蛋白标志物与弥散张量成像（DTI）和认知功能上轴突结构变化的相关性。具体而言，该项目旨在确定神经丝损伤（pNFH）和脂质调节（ApoA 1）标记物在轻度TBI后轴突损伤中的假定作用。轻度TBI和神经变性的长期风险增加之间的潜在联系将通过分析循环白细胞DNA的表观遗传变化来探索。 为了实现这些目标，PI建议召集一组参与接触性运动的大学运动员，其中轻度TBI是已知风险，以及一组中度至重度TBI患者，他们将外部脑室引流作为其临床护理的一部分。由于这项研究涉及轻度，中度和重度TBI后大脑结构和功能的几个方面的调查，因此它是指导对创伤性脑损伤感兴趣的新临床研究人员的理想平台。 该提案符合K24奖的目标，1）证明PI需要投入更多时间并增强其研究能力，2）提供理想的条件，指导新的临床研究者开展以患者为导向的研究。 公共卫生相关性：轻度TBI在美国是一个重要的公共卫生问题，目前没有客观的诊断帮助和治疗。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。轻度TBI可能导致思维和日常活动的问题，可能持续数月至数年。脑细胞受损的过程以及这种损伤如何与脑功能障碍联系在一起尚不完全清楚。这阻碍了可以改善受伤者生活的治疗方法的发展。PI建议检查血液和脊髓液的变化，以了解更多关于轻度TBI的信息。在这个过程中，他们希望培养和激励新一代对创伤性脑损伤感兴趣的临床研究人员。

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.