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.

项目概要/摘要 迫切需要确定支撑轻度脑外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开发 客观的预后生物标志物，使临床管理能够采用更加循证的方法 mTBI/SRC。已知脑损伤后炎症细胞因子会升高，导致产生 犬尿氨酸途径 (KP) 代谢物对大脑具有神经保护或神经毒性作用。效果 然而，SRC 对 KP 代谢物及其炎症介质的影响仍然未知。此举的目的 探索性 R21 提案旨在评估急性脑损伤背后的一种潜在病理生理机制 SRC 之后的行为变化。中心假设是 SRC 导致炎症诱导 神经毒性 KP 代谢物增加，与行为和功能的短期变化相关 海马体和内侧前额皮质（mPFC）的连接。这项研究的理由是 了解 SRC 后的代谢变化将有助于开发预后生物标志物和最终的结果 制定 SRC 患者的治疗策略。为了检验我们的假设，我们将利用血液， 来自现有联邦资助的高中和大学运动员项目的临床和神经影像数据。 可以获得受伤前基线以及 6 小时、2 天、8 天、15 天和 45 天的临床数据和血液 足球运动员受伤后。神经影像数据可在受伤后 2、8、15 和 45 天获得。未受伤 具有相同时间点的足球运动员作为对照，以及具有相同时间的非接触式运动运动员 点作为附加控制。我们将实现以下具体目标： 1）前瞻性地建立 神经毒性 KP 代谢物及其炎症介质从前到多的变化时间过程 脑震荡后访视，2) 确定这些代谢物与脑震荡后相关的程度 脑震荡症状报告和结果，以及 3) 确定这些代谢物的程度 与 mPFC 和海马功能连接的变化有关。该提案代表了 通过前瞻性地研究充分描述的角色的作用来研究 SRC 的科学创新方法 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 意义重大，因为它将激发一系列新的规划性研究，旨在确定 SRC 治疗的生理目标。