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

• 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
• 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

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（由申请方提供）：创伤性脑损伤导致代谢功能障碍，伴随氧化代谢和葡萄糖消耗的动态变化。目前缺乏对葡萄糖利用变化以外的代谢紊乱的更全面的理解。我们建议使用质谱分析代谢组-一套完整的初级和次级产品的细胞代谢-在小鼠模型的震荡。这种方法将同时表征数百种代谢物，包括参与葡萄糖代谢的代谢物（包括糖酵解和脂肪异生）、必需脂肪酸及其衍生物、维生素和氨基酸、克雷布斯循环成分、氧化应激和脂质过氧化途径标志物、炎症介质、脂质代谢产物（包括涉及脂肪酸合成、三酰甘油合成、磷脂和膜组分的那些）等。我们将使用我们实验室开发的重复性轻度脑震荡的已发表小鼠模型，该模型导致强大的认知缺陷，以研究认知功能障碍和代谢组学紊乱之间的关联。在目标1中，我们将比较损伤后急性（1天）和中间（6周）时间点的代谢组，以定义代谢补偿的演变。我们还将比较两种不同损伤严重程度下的代谢组。在目标2中，我们将研究脆弱期内的第二次损伤如何改变代谢变化解决的时间过程。我们将脑代谢物的分析与血清代谢组学数据相关联，以确定是否可以在外周血中监测脑代谢功能障碍。这些研究将扩大我们目前对脑震荡后代谢紊乱的认识，并提供对代谢恢复的潜在生物标志物的深入了解，以及减少重复性脑震荡神经后遗症的潜在治疗靶点。