Validation of Putative Serum of Axonal Damage After Mild TBI

轻度 TBI 后轴突损伤推定血清的验证

• 批准号: 8814120
• 负责人: JEFFREY John BAZARIAN
• 金额: $ 15.69万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8814120
• 关键词: Address; Affect; Afghanistan; Albumins; American; Anisotropy; Apolipoprotein A-I; Apolipoproteins; Award; Biochemical; Blood; Brain; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Characteristics; Clinical; Clinical Investigator; Cognitive deficits; Conflict (Psychology); DNA; DNA Damage; DNA Methylation; Diagnostic; Diffuse; Diffusion; Diffusion Magnetic Resonance Imaging; Epigenetic Process; Functional disorder; Generations; Goals; Gold; Histone Acetylation; Histones; Image; Injury; Investigation; Iraq; Learning; Leukocytes; Link; Lipids; Measures; Mentors; Methylation; Mid-Career Clinical Scientist Award (K24); Nerve Degeneration; Neurologic Dysfunctions; Pattern; Performance; Peripheral; Permeability; Process; Proteins; Public Health; Recovery; Regulation; Research; Research Personnel; Research Project Grants; Research Support; Risk; Role; Sampling; Serum; Serum Markers; Sports; Structure; Swelling; TBI Patients; Testing; Thinking; Time; Training; Traumatic Brain Injury; Validation; Ventricular; Ventriculostomy; axon injury; brain cell; career development; cell injury; circulating DNA; clinical care; cognitive function; cognitive performance; cognitive testing; cohort; college; differential expression; experience; improved; injured; insight; interest; meetings; mild traumatic brain injury; motor deficit; neurofilament; neuropathology; patient oriented research; prevent; public health relevance; response; standard measure; therapy development

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.

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进行以患者为导向的 TBI 研究。研究项目：轴突损伤被认为是轻度 TBI 后认知和运动缺陷的病理生理过程。该提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，并且对这些蛋白的检查可以深入了解轴突损伤的机制。该项目的目标是检查血液和脑脊液的变化，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）分析血清和脑脊液蛋白的暴露特征； 2) 轴突损伤的蛋白质标记物与扩散张量成像 (DTI) 和认知功能的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标记物 (pNFH) 和脂质调节标记物 (ApoA1) 在轻度 TBI 后轴突损伤中的假定作用。通过分析循环白细胞 DNA 的表观遗传变化，我们将探讨轻度 TBI 与神经退行性变长期风险增加之间的潜在联系。 为了实现这些目标，PI 建议组建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，他们在临床护理中放置了外脑室造口引流管。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多个方面的调查，因此它可以作为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。 该提案通过以下方式实现了 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，指导新的临床研究人员进行以下研究：以患者为中心的研究。 公共卫生相关性：轻度 TBI 是美国的一个重要公共卫生问题，目前尚无客观的诊断援助和治疗方法。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。轻度创伤性脑损伤可能会导致思维和日常活动出现问题，可持续数月至数年。脑细胞受损的过程以及这种损伤与脑功能障碍的关系尚不完全清楚。这阻碍了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 TBI 的信息。在此过程中，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。