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 迫切需要识别基于轻度创伤性脑的急性影响的分子途径 受伤（MTBI）和与运动有关的脑震荡（SRC）。这些信息最终将导致发展 客观，预后的生物标志物可以使更基于证据的方法来临床管理 mtbi/src。脑损伤后已知升高的炎症细胞因子导致产生 Kynurenine途径（KP）代谢产物对大脑具有神经保护作用或神经毒性作用。效果 然而，KP代谢物及其炎症介质的SRC仍然未知。这个目的 探索性R21建议是评估急性大脑背后的一种潜在的病理生理机制 SRC之后的行为变化。中心假设是SRC导致炎症诱导 与行为和功能的短期变化相关的神经毒性KP代谢产物的增加 海马和内侧前额叶皮层（MPFC）的连通性。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 为SRC患者开发治疗策略。为了检验我们的假设，我们将利用血液， 临床和神经影像学数据来自现有的联邦资助项目和大学运动员。 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天内获得 足球运动员受伤。神经影像学数据可在伤害后2、8、15和45天获得。无危机 时间点相同的足球运动员充当控制和非接触运动运动员的时间相同 点充当其他控件。我们将解决以下具体目标：1） 神经毒性KP代谢产物及其炎症介质从前到多个的变化的时间过程 脑震荡后访问，2）确定这些代谢物与后的程度 脑震荡症状的报告和结果，3）确定这些代谢产物的程度 与MPFC和海马功能连通性的变化有关。该建议代表 科学创新的研究SRC，通过前瞻性地研究了一个很好的描述的作用 代谢途径是SRC急性作用发病机理中潜在的最终常见途径。这 探索性R21很重要，因为它将刺激一系列旨在识别的程序化研究系列 SRC治疗治疗的生理靶标。