The role of neuroactive kynurenine metabolites in the chronic sequelae of concussion and contact sport exposure

神经活性犬尿氨酸代谢物在脑震荡和接触运动暴露的慢性后遗症中的作用

• 批准号: 10063064
• 负责人: Timothy B. Meier
• 金额: $ 36万
• 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: 2017-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063064
• 关键词: Address; Adult; Age; Agonist; Anhedonia; Anisotropy; Anterior; Behavior; Bipolar Disorder; Blood; Blood specimen; Brain; Brain Concussion; Chronic; Clinical; Cognitive; Corpus Callosum; Craniocerebral Trauma; Data; Development; Diagnosis; Disease; Enrollment; Evaluation; Exposure to; Female; Free Radicals; Functional disorder; Glutamates; Hippocampus (Brain); Impairment; Kynurenic Acid; Kynurenine; Lead; Limbic System; Long-Term Effects; Major Depressive Disorder; Measures; Mental disorders; Metabolic Pathway; Molecular; Moods; N-Methyl-D-Aspartate Receptors; National Institute of Neurological Disorders and Stroke; Neurodegenerative Disorders; Neurosciences Research; Pathway interactions; Patient Self-Report; Pharmacologic Substance; Play; Prognostic Marker; Public Health; Quinolinic Acid; Research; Rest; Risk; Role; Structural defect; Structure; Symptoms; Testing; Thick; Translational Research; Visit; Work; base; cingulate cortex; cognitive performance; concussive symptom; contact sports; head impact; innovation; male; neurobehavioral; neuroimaging; neuropsychiatry; neurotoxic; prevent; psychologic; translational approach

Project Summary/Abstract There is an urgent need to characterize the long-term effects of contact sport exposure with and without prior concussion, and to identify potential molecular mechanisms that may underlie these effects. An imbalance in glutamatergic activity caused by neuroactive kynurenine pathway metabolites is one such mechanism behind abnormalities of limbic system structure and function in a variety of disorders. The objective of this proposal is to elucidate the relationship between neuroactive kynurenine pathway metabolites and chronic abnormalities in the limbic system associated with repetitive concussion and head impact exposure from contact sport participation. The central hypothesis is that prior concussion and/or exposure to contact sport lead to structural and functional alterations in a limbic system centered on the rostral anterior cingulate cortex and hippocampus resulting in sub-clinical mood-dysregulation, and that these changes are driven by neurotoxic kynurenine pathway metabolites in the brain that are reflected by concentrations in blood. Male and female adults (age 18- 26) will be enrolled across three groups, including (1) contact sport athletes with a prior concussion, (2) contact sport athletes with no prior concussion, and (3) non-contact sport athletes to separate the effects of contact sport exposure with and without previous concussion. An advanced neuroimaging battery, a clinical battery, and blood specimen will be collected in a single visit to address the following aims: (Aim 1) Test the hypothesis that concussion and contact sport exposure are associated with structural differences in the limbic system that correlate with neuroactive KP metabolites, and (Aim 2) Test the hypothesis that concussion and contact sport exposure are associated with differences in limbic system functional connectivity and behavior that correlate with neuroactive KP metabolites. We expect that this work will delineate the potential role of neuroactive KP metabolites in the neurobiobehavioral sequelae of concussion and contact sport exposure for the millions of athletes currently participating in contact sport. This information is of major public health significance because it will stimulate bidirectional translational research that will ultimately lead to the development of pharmaceutical treatments to prevent or reverse these effects in at-risk contact sport athletes. This hypothesis- driven proposal is scientifically innovative because it will study the relationship between the long-term effects of concussion/head impact exposure and one molecular pathway implicated in limbic system dysregulation in parallel neuroscience research. !

项目摘要/摘要 迫切需要确定接触运动暴露的长期影响的特征。 脑震荡，并确定可能构成这些影响的潜在分子机制。一种不平衡 神经活性犬尿氨酸途径代谢产物引起的谷氨酸能活动是这种机制之一 各种疾病中边缘系统结构和功能的异常。这项提议的目标是 探讨犬尿氨酸途径神经活性代谢产物与慢性肾功能异常的关系 与反复脑震荡和接触运动头部撞击暴露相关的边缘系统 参与。中心假设是，先前脑震荡和/或接触接触运动会导致结构性 以嘴前扣带回皮质和海马体为中心的边缘系统的功能改变 导致亚临床情绪失调，这些变化是由神经毒性犬尿氨酸驱动的 大脑中的代谢物，由血液中的浓度反映。成年男性和女性(18岁- 26)将分三组招募，包括(1)有脑震荡史的接触性运动运动员，(2)接触性 运动运动员无脑震荡前科，和(3)非接触性运动运动员分开接触的影响 有或没有脑震荡的运动暴露。先进的神经成像电池，临床电池， 并将在一次访问中收集血液样本，以实现以下目标：(目标1)检验假设 脑震荡和接触运动暴露与边缘系统的结构差异有关 与神经活性KP代谢物相关，并(目标2)检验脑震荡和接触运动的假设 暴露与边缘系统功能连通性和相关行为的差异有关 有神经活性的KP代谢物。我们期望这项工作将描述神经活性KP的潜在作用。 数百万人脑震荡和接触运动暴露的神经生物行为后遗症中的代谢物 目前正在参加接触性运动的运动员。这一信息具有重大的公共卫生意义，因为 它将刺激双向翻译研究，最终将导致 对有危险接触的运动运动员进行药物治疗以防止或逆转这些影响。这个假设-- 驱动型提案具有科学创新性，因为它将研究 脑震荡/头部撞击暴露和与边缘系统失调有关的一个分子通路 平行的神经科学研究。 好了！