Role of fatty acid oxidation after pediatric head injury

小儿颅脑损伤后脂肪酸氧化的作用

• 批准号: 10574508
• 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: 2019-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574508
• 关键词: Acetyl Coenzyme A; Address; Adult; Affect; Apoptosis; Area; Astrocytes; Attention; Behavioral; Biochemical; Bioenergetics; Brain; Brain Injuries; Brain region; Carnitine; Cell Death; Cell Respiration; Cell Survival; Cell membrane; Cerebrum; Cessation of life; Child; Childhood; Childhood Injury; Citric Acid Cycle; Craniocerebral Trauma; Critical Pathways; Data; Development; Enzymes; Epidemic; Fatty Acids; Gene Expression; Genetic; Glucose; Goals; Hippocampus; Histological Techniques; Hour; Impairment; Inflammation; Injury; Intervention; Learning; Levocarnitine; Life; Mediating; Memory; Metabolic; Metabolism; Mission; Mitochondria; Modeling; National Institute of Neurological Disorders and Stroke; Nervous System Physiology; Nervous System Trauma; Neurologic; Neurological outcome; Neurons; Neurotransmitters; Nonesterified Fatty Acids; Outcome; Outer Mitochondrial Membrane; Pathway interactions; Play; Process; Production; Proteins; Public Health; Quality of life; Rattus; Recovery; Recovery of Function; Reporting; Research; Role; Survivors; Synapses; Testing; Therapeutic; Transferase; Trauma; Traumatic Brain Injury; Traumatic Brain Injury recovery; Up-Regulation; acylcarnitine; cognitive ability; controlled cortical impact; cost; fatty acid metabolism; fatty acid oxidation; glucose metabolism; healing; improved; improved outcome; injured; interdisciplinary approach; long chain fatty acid; meetings; mitochondrial membrane; myelination; neurogenesis; neurological recovery; neuron loss; neuroprotection; novel therapeutic intervention; oxidation; pediatric traumatic brain injury; pharmacologic; postnatal; pup; side effect; synaptogenesis

Project Summary Pediatric traumatic brain injury (TBI) is a “silent epidemic” affecting over 500,000 children each year. Metabolic crisis due to impaired oxidative glucose metabolism is a hallmark of TBI. Metabolism is indispensable for proper brain development and function, however, metabolic demands superimposed by trauma during these crucial periods of brain development result in secondary injury and further impaired neurological function. Emergent evidence and our preliminary data show that brain is capable of oxidizing fatty acids via mitochondrial β-oxidation and this process is developmentally regulated. Our preliminary data show, that while brain glucose metabolism is decreased following TBI, fatty acid oxidation is increased in the injured brain. Our hypothesis is that pharmacological or genetic up-regulation of brain's fatty acids oxidation is a critical metabolic and neuroprotective target, which can support brain energy and metabolism during metabolic crisis. Using pediatric model of severe brain injury, we aim to test this hypothesis and determine the extent to which fatty acid oxidation may support oxidative metabolism after TBI. Therefore, we propose to: 1) quantify brain temporal and regional abilities to oxidize fatty acid after TBI; 2) determine that pharmacological or genetic increase of fatty acid oxidation will result in improved bioenergetics after TBI; 3) establish that improved neurological function and decreased extent of injury are due to increased metabolic support via increased fatty acid oxidation. To address this important, but still unanswered question, we will use multi-disciplinary approach and combine biochemical, genetic, behavioral and histological techniques. The aim of this research to decipher brain's innate attempts to meet metabolic demands after the injury and pharmacologically amplify them towards meaningful improvement of neurological recovery and activities of daily life.

项目摘要 小儿创伤性脑损伤（TBI）是一种“无声的流行病”，每年影响50多万儿童。代谢 由于氧化葡萄糖代谢受损而导致的危象是TBI的标志。新陈代谢是必不可少的， 然而，正常的大脑发育和功能，在这些过程中， 大脑发育的关键时期导致继发性损伤和进一步受损的神经功能。 新出现的证据和我们的初步数据表明，大脑能够通过氧化脂肪酸， 线粒体β-氧化，这一过程受到发育调节。初步数据显示， 脑葡萄糖代谢在TBI后降低，受伤的脑中脂肪酸氧化增加。我们 一种假说认为，大脑脂肪酸氧化的药理学或遗传学上调是一种关键的代谢过程， 和神经保护靶点，在代谢危机时支持脑能量和代谢。使用 我们的目的是测试这一假设，并确定脂肪在多大程度上影响了严重脑损伤的儿童模型。 酸氧化可支持TBI后的氧化代谢。因此，我们建议：1）量化大脑 TBI后氧化脂肪酸时间和区域能力; 2）确定药理或遗传 脂肪酸氧化的增加将导致TBI后生物能量学的改善; 3）建立改善的 神经功能和损伤程度的降低是由于通过增加脂肪酸而增加代谢支持。 酸氧化为了解决这一重要但尚未得到解答的问题，我们将采用多学科方法 并结合联合收割机生物化学、遗传学、行为学和组织学技术。这项研究的目的是 大脑在受伤后满足代谢需求的本能尝试， 有意义地改善神经恢复和日常生活活动。