Inflammation and Kynurenine Metabolites in the Acute Sequelae of Concussion

脑震荡急性后遗症中的炎症和犬尿氨酸代谢物

• 批准号: 9506873
• 负责人: Timothy B. Meier
• 金额: $ 19.65万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9506873
• 关键词: Acute; Address; Affect; Agonist; Athletic Injuries; Behavior; Behavioral; Blood; Brain; Brain Concussion; Brain Injuries; Clinical; Clinical Data; Clinical Management; Craniocerebral Trauma; Data; Development; Disease; Ensure; Funding; Guidelines; Hippocampus (Brain); Hour; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interferon Type II; Interleukin-1 Receptors; Interleukin-1 beta; Knowledge; Kynurenic Acid; Kynurenine; Lead; Link; Manufactured football; Measures; Medial; Metabolic; Metabolic Pathway; Metabolism; Molecular; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; National Institute of Neurological Disorders and Stroke; Neurobiology; Outcome; Pathogenesis; Pathway interactions; Patients; Physiological; Post-Concussion Syndrome; Prefrontal Cortex; Production; Prognostic Marker; Proxy; Public Health; Quinolinic Acid; Reporting; Research; Rest; Role; Safety; Sports; TNF gene; Testing; Time; Visit; Work; base; brain abnormalities; clinical decision-making; cohort; college; concussive symptom; cytokine; design; evidence base; follow-up; high school; inflammatory marker; innovation; mild traumatic brain injury; mood symptom; neuroimaging; neurotoxic; pre-clinical; prevent; prospective; psychological distress; targeted treatment; therapeutic development; therapeutic target; translational impact

Project Summary/Abstract There is a pressing need to identify molecular pathways underpinning the acute effects of mild traumatic brain injury (mTBI) and sport-related concussion (SRC). This information will ultimately lead to the development of objective, prognostic biomarkers to enable a more evidence-based approach to the clinical management of mTBI/SRC. Inflammatory cytokines known to be elevated following brain injury lead to the production of kynurenine pathway (KP) metabolites that have neuroprotective or neurotoxic effects on the brain. The effects of SRC on KP metabolites and their inflammatory mediators, however, remain unknown. The objective of this exploratory R21 proposal is to evaluate one potential pathophysiological mechanism behind acute brain and behavioral changes following SRC. The central hypothesis is that SRC leads to inflammation-induced increases in neurotoxic KP metabolites that are associated with short-term changes in behavior and functional connectivity of the hippocampus and medial prefrontal cortex (mPFC). The rationale for this research is that understanding metabolic changes following SRC will aid development of prognostic biomarkers and eventual development of therapeutic strategies for patients with SRC. To test our hypotheses, we will leverage blood, clinical, and neuroimaging data from an existing federally funded project on high school and collegiate athletes. Clinical data and blood is available at pre-injury baseline and at 6 hours, 2 days, 8 days, 15 days, and 45 days post-injury in football players. Neuroimaging data is available at 2, 8, 15, and 45 days post-injury. Non-injured football players with identical time points serve as controls and non-contact sport athletes with identical time points serve as additional controls. We will address the following specific aims: 1) Prospectively establish the time course of changes in neurotoxic KP metabolites and their inflammatory mediators from pre- to multiple post-concussion visits, 2) Determine the extent to which these metabolites are associated with post- concussion symptom reporting and outcome, and 3) Determine the extent to which these metabolites are associated with changes in functional connectivity of the mPFC and hippocampus. This proposal represents a scientifically innovative approach to study SRC by prospectively investigating the role of a well-described metabolic pathway as a potential final common pathway in the pathogenesis of the acute effects of SRC. This exploratory R21 is significant because it will stimulate a new line of programmatic research aimed at identifying physiological targets for therapeutic treatment of SRC.

项目摘要/摘要 迫切需要确定支持轻度创伤性脑损伤急性影响的分子途径。 损伤(MTBI)和运动相关脑震荡(SRC)。这些信息最终将导致 客观、可预测预后的生物标志物使临床治疗更加循证。 MTBI/SRC。已知的脑损伤后炎性细胞因子升高导致脑组织产生 犬尿氨酸途径(KP)对大脑具有神经保护或神经毒性作用的代谢物。其影响 然而，SRC对KP代谢物及其炎症介质的作用仍不清楚。这样做的目的是 探索性的R21建议是评估急性脑出血和脑出血背后的一个潜在的病理生理机制。 SRC后的行为改变。中心假设是SRC导致炎症诱导 与短期行为和功能改变相关的神经毒性KP代谢物的增加 海马体和内侧前额叶皮质(MPFC)的连接。这项研究的基本原理是 了解SRC后的代谢变化将有助于预后生物标志物的开发和最终 SRC患者治疗策略的发展。为了检验我们的假设，我们将利用血液， 临床和神经成像数据来自一个现有的联邦资助的高中和大学运动员项目。 临床数据和血液可在受伤前基线以及6小时、2天、8天、15天和45天获得 足球运动员的受伤后。神经影像数据可在损伤后2、8、15和45天获得。无人受伤 相同时间点的足球运动员为对照组，时间相同的非接触性体育运动员为对照组 点可用作附加控件。我们将解决以下具体目标：1)前瞻性地建立 神经毒性KP代谢物及其炎性介质从Pre-Pre-My变化的时程 脑震荡后的访问，2)确定这些代谢物与脑震荡后的 脑震荡症状报告和结果，以及3)确定这些代谢物 与mPFC和海马区功能连接的变化有关。这项提议代表着 以科学创新的方法通过前瞻性调查研究SRC的作用 代谢途径是SRC急性效应发病机制中潜在的最终共同途径。这 探索性R21具有重要意义，因为它将激发一系列旨在确定 SRC治疗的生理指标。