Coordination of fatty acid metabolism following neonatal brain injury from preterm birth

早产新生儿脑损伤后脂肪酸代谢的协调

• 批准号: 10641924
• 负责人: Joseph Scafidi
• 金额: $ 39.55万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641924
• 关键词: Acute; Biochemical; Brain; Brain Injuries; Brain region; Carnitine Palmitoyltransferase I; Cell Maturation; Cells; Cerebrum; Clinical Management; Critical Pathways; Data; Dependence; Development; Energy-Generating Resources; Ensure; Equilibrium; Essential Fatty Acids; Failure; Fatty Acids; Genes; Glucose; Goals; Growth; Hippocampus; Histologic; Hypoxia; Image; Impairment; Inflammatory; Injury; Knowledge; Life; Lipid Peroxidation; Lipids; Measures; Membrane Lipids; Metabolic; Metabolism; Mission; Mitochondria; Neonatal; Neonatal Brain Injury; Nervous System Trauma; Neurological outcome; Organ; Outcome Study; Pathway interactions; Phase; Phenotype; Play; Population; Premature Birth; Process; Production; Proliferating; Proteins; RNA; Reactive Oxygen Species; Recovery; Recovery of Function; Research; Role; Science; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Testing; Therapeutic; Time; United States National Institutes of Health; acylcarnitine; behavioral study; brain metabolism; density; dietary; experience; extreme prematurity; fatty acid metabolism; fatty acid oxidation; fetal; flexibility; functional outcomes; improved; inducible Cre; inflammatory marker; mass spectrometric imaging; migration; myelination; neonatal period; nerve stem cell; neural; neurobehavioral; neurogenesis; new therapeutic target; novel therapeutics; oxidation; postnatal; response; response to injury; stem; stem cells; subventricular zone; tandem mass spectrometry; treatment strategy; white matter

Fatty acids (FAs) are essential in the developing brain for myelination, neurogenesis, and lipid membrane turnover. During fetal and early postnatal brain development, FA synthesis in the brain is necessary for rapid structural brain growth. However, FAs can also serve as a source of energy. Recent evidence suggests that neural stem and progenitor cells rely largely on FA oxidation for energy. The question is whether the balance between FA synthesis and oxidation (FA metabolism) in the brain shifts after injury. Neonatal brain injury is a major contributor to long-term neurodevelopmental delays. The response to injury and endogenous recovery phase is metabolically expensive, imposing additional energy demands and disrupting the highly orchestrated process of brain development and maturation. Therefore, there is a critical need to delineate acute and long- term metabolic adaptations after neonatal brain injury. Our preliminary results show that the neonatal injured brain from intermittent hypoxia has decreased FA composition, increased dependency on FAs as a fuel compared to other substrates and increased FA oxidation. In addition, FA mobilization for oxidation is increased days after injury. Based on these results, we hypothesize that metabolic adaptations after neonatal brain injury directly perturb the balance of FA synthesis and oxidation, thereby disrupting the timely developmental trajectory of brain growth and maturation. We will test our hypothesis in three aims. In the first aim, we will determine temporal and spatial contributions of FA metabolism after neonatal brain injury. This aim will delineate time- and region-specific FA composition in the hippocampus, white matter, and subventricular zone. The region-specific composition of FAs and substrates will be measured with tandem mass spectrometry and MALDI- mass spectrometry imaging. We will measure protein, RNA, and metabolic flux in region- and cell-specific populations. Studies will be performed that will measure dependency, capacity, and flexibility to utilize FAs and other substrates from different brain regions and time points after injury. In the second aim, we will determine whether time-specific alteration of FA metabolism in progenitor cells disrupts their normal developmental trajectory. We will specifically remove an obligate gene responsible for FA synthesis or oxidation in neural progenitor cells to answer the question whether FA metabolism regulates neural progenitor cell activity in the neurogenic niches. In the third aim, we will test whether brain FA oxidation after neonatal brain injury is adaptive or maladaptive. This aim will study the role of FA oxidation in the developing brain and after neonatal brain injury using pan- brain-specific loss of either the obligate gene in FA oxidation or the gene responsible for the rate-limiting step of FA translocation into the mitochondria. Overall, this project will delineate the time-course and contribution of FAs toward metabolic flexibility. The outcomes of this study will inform the science of FA metabolism and guide development of new therapeutic targets aimed at balancing metabolic demands after neonatal brain injury.

脂肪酸（FAs）是大脑发育中髓鞘形成、神经发生和脂质膜所必需的