Validation of Putative Serum of Axonal Damage After Mild TBI

描述（由申请人提供）：研究目标：检测创伤性轴索损伤（AI）的推定蛋白标志物，以阐明轻度创伤性脑损伤（mild traumatic brain injury， 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人员，并在TBI中进行以患者为导向的研究。研究项目：轴突损伤被认为是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）蛋白的差异表达，对这些蛋白的检查可以深入了解轴突损伤的机制。该项目的目的是检查血液和脑脊液的变化，以测试与轻度创伤性脑损伤的生化和细胞反应有关的几种假设。这一目标将通过两种调查策略来实现：1)分析血清和脑脊液蛋白的暴露特征；2)轴突损伤蛋白标志物与轴突弥散张量成像（DTI）结构变化及认知功能的相关性。具体来说，本项目旨在确定轻度脑外伤后神经丝损伤标志物（pNFH）和脂质调节标志物（ApoA1）在轴突损伤中的作用。轻度创伤性脑损伤与神经退行性变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建议召集一组参加接触性运动的大学运动员，其中轻度TBI是已知的风险，以及一组中度至重度TBI患者，这些患者将外脑室造口引流作为其临床护理的一部分。由于本研究涉及轻度、中度和重度脑外伤后脑结构和功能的多个方面的研究，为对创伤性脑损伤感兴趣的新临床研究者提供了一个理想的指导平台。该提案符合K24奖的目标，1)表明PI需要投入更多的时间来增强他的研究能力，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。

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.