Mechanisms of metabolic adaptation after traumatic brain injury

脑外伤后代谢适应机制

• 批准号: 10090659
• 负责人: Susanna Scafidi
• 金额: $ 35.82万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090659
• 关键词: Acute; Astrocytes; Basic Science; Biochemistry; Blood - brain barrier anatomy; Brain; Brain Injuries; Brain region; Carnitine; Cell membrane; Cells; Cognitive; Complex; Data; Energy Metabolism; Energy-Generating Resources; Exhibits; Fasting; Fatty Acids; Functional disorder; Glucose; Goals; Hepatic; Hyperglycemia; Impairment; Inflammation; Injury; Intervention; Ketones; Knockout Mice; Knowledge; Lead; Learning; Lesion; Life; Lipid Peroxidation; Lipids; Measures; Memory; Messenger RNA; Metabolic; Mission; Mitochondria; Modeling; Modernization; Motor; Mus; National Institute of Neurological Disorders and Stroke; Nerve Tissue; Nervous System Trauma; Nervous system structure; Neuraxis; Neurologic; Neurons; Nonesterified Fatty Acids; Oxides; Pathway interactions; Patients; Physiological; Proteins; Public Health; Quality of life; Recovery; Recovery of Function; Regulation; Research; Rest; Role; Supportive care; Testing; Therapeutic Intervention; Time; Tissues; Transgenic Mice; Traumatic Brain Injury; Up-Regulation; base; cell type; disability; experimental study; fatty acid metabolism; fatty acid oxidation; glucose metabolism; improved; in vivo; injured; ketogenesis; lipid metabolism; mouse genetics; mouse model; nerve injury; nerve stem cell; novel therapeutic intervention; oxidation; repaired; response; targeted treatment; therapeutically effective

PROJECT SUMMARY / ABSTRACT Traumatic brain injury (TBI) results in life-long cognitive and motor disabilities. TBI elicits acute and prolonged metabolic adaptations in an attempt to provide physiological fuel and to enable the survival of damaged nervous tissue. The overall objective of this proposal is to determine the mechanisms of metabolic adaptation to injury and the metabolic requirements that promote recovery following TBI. The pathophysiology of TBI is complex and characterized largely by dysregulated glucose metabolism. However, brain contains high concentration of fatty acids, which are liberated from plasma membrane following TBI and further propagate secondary injury by promoting inflammation and lipid peroxidation. We have shown that brain is capable of utilizing these fatty acids for energy and metabolism via β-oxidation. Specifically, this mechanism is present in neural progenitor cells and astrocytes. Thus, this mechanism allows to re-direct fatty acids to mitochondria for β-oxidation. Importantly, our preliminary data show that fatty acid oxidation is increased following traumatic brain injury. We hypothesize that the injured brain requires the up-regulation of fatty acid oxidation specifically in astrocytes in order to spare glucose for neurons as well as eliminating toxic fatty acid intermediates following damage to nervous tissue and blood brain barrier. Using tissue specific transgenic and knockout mouse models, we will test this hypothesis and detail these fundamental unanswered questions. To test these hypothesis we propose three specific aims: 1) Determine the spatial and temporal contribution of brain fatty acid metabolism following TBI; 2) Determine the requirement for brain fatty acid oxidation following TBI; 3) Determine the requirements for systemic metabolic adaptations following TBI. The long-term goal of this project is to determine the regulation and requirement for fatty acid oxidation pathway following TBI. Thus, these studies will elucidate how fatty acid metabolism is regulated following the injury and advance our understanding of metabolic adaptations. Furthermore, the fundamental knowledge how fatty acid metabolism is altered after TBI could lead to targeted therapies to improve brain energy and metabolism after neurological insult. !

项目摘要 /摘要 创伤性脑损伤（TBI）导致终身认知和运动障碍。 TBI引起急性和 长时间的代谢适应以提供物理燃料并实现生存 神经组织受损。该提案的总体目的是确定 对损伤的代谢适应和促进TBI后恢复的代谢需求。 TBI的病理生理学是复杂的，并且在很大程度上以失调的葡萄糖为特征 代谢。但是，大脑含有高浓度的脂肪酸，这些脂肪酸从 TBI之后的质膜，并通过促进感染进一步传播继发损伤 和脂质过氧化。我们已经证明大脑能够利用这些脂肪酸进行能量 通过β氧化代谢。具体而言，该机制在神经祖细胞和 星形胶质细胞。这就是该机制可以将脂肪酸重新引导到线粒体以进行β氧化。 重要的是，我们的初步数据表明，脑外伤后脂肪酸氧化增加了 受伤。我们假设受伤的大脑需要上调脂肪酸氧化 特别是在星形胶质细胞中，以备神经元的葡萄糖以及消除有毒脂肪酸 损害神经组织和血脑屏障后的中间体。使用特定于组织 转基因和敲除鼠标模型，我们将检验此假设并详细介绍这些基本 未解决的问题。为了检验这些假设，我们提出了三个具体目的：1）确定 TBI后，脑脂肪酸代谢的空间和暂时贡献； 2）确定 TBI后脑脂肪酸氧化的要求； 3）确定系统性的要求 TBI后的代谢适应。该项目的长期目标是确定法规 TBI之后对脂肪酸氧化途径的要求。那就是这些研究将阐明 受伤后调节脂肪酸代谢，并提高我们对代谢的理解 改编。此外，基本知识在TBI之后如何改变脂肪酸代谢 可能导致有针对性的疗法改善神经系统侮辱后的大脑能量和代谢。 呢