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）在发育中的脑中对于髓鞘形成、神经发生和脂质膜是必需的 周转在胎儿和出生后早期的大脑发育过程中，大脑中FA的合成是快速发育所必需的。 结构性大脑发育然而，脂肪酸也可以作为能源。最近的证据表明 神经干细胞和祖细胞主要依赖于FA氧化提供能量。问题是， 在脑损伤后，FA合成和氧化（FA代谢）之间的变化。新生儿脑损伤是 长期神经发育迟缓的主要原因。对损伤的反应和内源性恢复 代谢阶段是昂贵的，施加额外的能量需求，破坏高度协调的 大脑发育和成熟的过程。因此，迫切需要划定急性和长期的- 新生儿脑损伤后的长期代谢适应。我们的初步结果显示，新生儿受伤 间歇性缺氧导致大脑FA成分减少，对FA作为燃料的依赖性增加 与其他底物相比，FA氧化增加。此外，用于氧化的FA动员增加 受伤后的几天基于这些结果，我们假设新生儿脑损伤后的代谢适应 直接扰乱FA合成和氧化的平衡，从而破坏及时的发育轨迹 大脑的生长和成熟。我们将从三个方面来检验我们的假设。在第一个目标中，我们将确定 新生儿脑损伤后FA代谢的时空贡献这一目标将界定时间， 海马、白色物质和脑室下区的区域特异性FA组成。述特定于地区 FA和底物的组成将用串联质谱法和MALDI-质谱法测量。 光谱成像我们将测量区域和细胞特异性群体中的蛋白质，RNA和代谢通量。 将进行研究，以衡量依赖性，能力和灵活性，利用FA和其他 损伤后不同脑区和时间点的底物。在第二个目标中，我们将确定 祖细胞中FA代谢的时间特异性改变破坏了它们的正常发育轨迹。我们 将特异性地去除神经祖细胞中负责FA合成或氧化的专性基因， 回答FA代谢是否调节神经原性龛中的神经祖细胞活性的问题。 在第三个目标中，我们将测试新生儿脑损伤后的脑FA氧化是否是适应性的或不适应的。 本研究的目的是研究FA氧化在发育中的脑和新生儿脑损伤后的作用， 大脑特异性的损失，无论是专性基因在FA氧化或基因负责的限速步骤， FA易位进入线粒体。总的来说，本项目将描述FA的时间进程和贡献 代谢的灵活性。这项研究的结果将为FA代谢科学提供信息， 开发新的治疗靶点，旨在平衡新生儿脑损伤后的代谢需求。