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

描述（申请人提供）：外伤性脑损伤导致代谢功能紊乱，氧化代谢和葡萄糖消耗发生动态变化。目前还缺乏对葡萄糖利用变化之外的代谢紊乱的更全面的了解。我们建议使用质谱法分析小鼠脑震荡模型中的代谢组-细胞代谢的全套初级和次级产物。该方法将同时表征数百种代谢物，包括参与糖代谢的代谢物（包括糖酵解和糖异生）、必需脂肪酸及其衍生物、维生素和氨基酸、克雷布斯循环组分、氧化应激和脂质过氧化途径标志物、炎症介质、脂质代谢物（包括参与脂肪酸合成、三酰甘油合成、磷脂和膜组分）等。为了研究认知功能障碍和代谢紊乱之间的关系，我们将使用我们实验室开发的重复性轻度脑震荡小鼠模型，该模型会导致严重的认知缺陷。在目的1中，我们将比较损伤后急性（1天）和中期（6周）时间点的代谢组，以确定代谢代偿的演变。我们还将比较两种不同程度损伤严重程度的代谢组。在Aim 2中，我们将研究易损期的第二次损伤如何改变代谢变化的时间进程。我们将把脑代谢物的分析与血清代谢组学数据联系起来，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，并为代谢恢复的潜在生物标志物以及减少重复性脑震荡神经系统后遗症的潜在治疗靶点提供见解。

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.