Characterization of the Brain and Serum Metabolome in Mouse Models of Concussion

脑震荡小鼠模型中大脑和血清代谢组的表征

基本信息

批准号：
8786482
负责人：
MICHAEL J WHALEN
金额：
$ 8.69万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8786482
关键词：
Acute Amino Acids Animals Biochemical Biological Markers Brain Brain Concussion Brain Injuries Cell Respiration Cerebrum Charge Child Citric Acid Cycle Closed head injuries Cognitive Cognitive deficits Consumption Data Drops Essential Fatty Acids Evolution Fatty Acids Financial compensation Functional disorder Gas Chromatography Gluconeogenesis Glucose Glycolysis Goals Health Height Human Impaired cognition Inflammation Mediators Injury Knowledge Libraries Lipid Peroxidation Lipids Mass Spectrum Analysis Measurable Membrane Mental Depression Metabolic Metabolism Mild Concussions Modeling Monitor Mus Neurologic Outcome Oxidative Stress Oxygen Pathway interactions Phospholipids Public Health Publishing Recovery Recurrence Reporting Research Personnel Resolution Risk Sampling Seizures Serum Severities Testing Time Traumatic Brain Injury Triglycerides Unconscious State Vitamins Weight base design glucose metabolism indexing insight liquid chromatography mass spectrometry metabolic abnormality assessment metabolic rate metabolomics mild traumatic brain injury mortality mouse model peripheral blood prevent response targeted treatment therapeutic target tool young adult

项目摘要

DESCRIPTION (provided by applicant): Traumatic brain injury results in a state of metabolic dysfunction with dynamic changes in oxidative metabolism and glucose consumption. A more comprehensive understanding of the metabolic derangements beyond changes in glucose utilization is currently lacking. We propose to use mass spectrometry to analyze the metabolome - the complete set of primary and secondary products of cellular metabolism - in a murine model of concussion. This approach will characterize hundreds of metabolites simultaneously, including those involved in glucose metabolism (including glycolysis and gluconeogenesis), essential fatty acids and their derivatives, vitamins and amino acids, Krebs cycle components, oxidative stress and lipid peroxidation pathway markers, inflammatory mediators, lipid metabolites (including those involved in fatty acid synthesis, triacylglycerol synthesis, phospholipids and membrane components), among others. We will use a published mouse model of repetitive mild concussion developed in our lab that results in robust cognitive deficits, in order to study the association between cognitive dysfunction and metabolomic derangements. In Aim 1, we will compare the metabolome at both acute (1 day) and intermediate (6 week) time points post- injury to define the evolution of metabolic compensation. We will also compare the metabolome at two different levels of injury severity. In Aim 2, we will study how a second injury within the vulnerable period alters the time course of resolution of metabolic changes. We will correlate our analysis of brain metabolites with serum metabolomic data to determine whether metabolic dysfunction of the brain can be monitored in peripheral blood. These studies will expand our current knowledge of post-concussive metabolic derangement and provide insight into potential biomarkers of metabolic recovery, as well as potential therapeutic targets to reduce neurological sequelae of repetitive concussion.

描述（由申请人提供）：创伤性脑损伤导致代谢功能障碍的状态，氧化代谢和葡萄糖消耗的动态变化。目前缺乏超出葡萄糖利用率变化的代谢危险的更全面的理解。我们建议在脑震荡模型中使用质谱法分析细胞代谢的代谢组（细胞代谢的一组和次要产物）。这种方法将同时表征数百种代谢产物，包括参与葡萄糖代谢（包括糖酵解和糖原生成），必需脂肪酸及其衍生物，维生素和氨基酸的循环成分，氧化应激和脂质过氧化途径，炎症概念，脂肪含量，脂肪含量，脂肪含量，脂肪酸和氨基酸的成分（包括糖酵解和糖原生成），脂肪酸和氨基酸循环成分（包括氧化型和氨基酸）。三酰基甘油合成，磷脂和膜成分）等。我们将使用在我们的实验室中开发的重复轻度脑震荡的公开小鼠模型，该模型导致强大的认知缺陷，以研究认知功能障碍与代谢组扰动之间的关联。在AIM 1中，我们将比较急性（1天）和中间（6周）时间点的代谢组，以定义代谢补偿的演变。我们还将在两种不同水平的损伤严重程度下比较代谢组。在AIM 2中，我们将研究脆弱时期内的第二次伤害如何改变代谢变化的时间过程。我们将将对脑代谢产物的分析与血清代谢组数据相关联，以确定是否可以在外周血中监测大脑的代谢功能障碍。这些研究将扩大我们当前对脑震荡的代谢危险的了解，并洞悉代谢恢复的潜在生物标志物，以及潜在的治疗靶标，以减少重复性脑震荡的神经系统后遗症。