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. !

项目总结/摘要 创伤性脑损伤（TBI）导致终身的认知和运动障碍。TBI急性发作， 延长代谢适应，试图提供生理燃料，使生存 受损的神经组织本提案的总体目标是确定 对损伤的代谢适应和促进TBI后恢复的代谢要求。 TBI的病理生理学是复杂的，其特征主要是血糖失调 新陈代谢.然而，大脑中含有高浓度的脂肪酸，这些脂肪酸是从 TBI后的质膜，并通过促进炎症进一步传播继发性损伤 和脂质过氧化作用。我们已经证明，大脑能够利用这些脂肪酸的能量 和通过β-氧化代谢。具体地说，这种机制存在于神经祖细胞中， 星形胶质细胞因此，这种机制允许将脂肪酸重新引导至线粒体进行β-氧化。 重要的是，我们的初步数据显示，脑外伤后脂肪酸氧化增加， 损伤我们假设受伤的大脑需要脂肪酸氧化的上调 特别是在星形胶质细胞中，以便为神经元节省葡萄糖以及消除有毒脂肪酸 神经组织和血脑屏障损伤后的中间体。使用组织特异性 转基因和基因敲除小鼠模型，我们将测试这一假设，并详细说明这些基本 没有答案的问题为了验证这些假设，我们提出了三个具体目标：1）确定 TBI后脑脂肪酸代谢的空间和时间贡献; 2）确定TBI后脑脂肪酸代谢的空间和时间贡献。 TBI后脑脂肪酸氧化的要求; 3）确定全身性脂肪酸氧化的要求。 脑外伤后的代谢适应该项目的长期目标是确定监管 和TBI后脂肪酸氧化途径的需要。因此，这些研究将阐明如何 脂肪酸代谢在损伤后受到调节，并促进我们对代谢的理解。 适应此外，TBI后脂肪酸代谢如何改变的基本知识 可能导致靶向治疗，以改善神经损伤后的大脑能量和代谢。 !