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)在发育中的大脑中对髓鞘形成、神经发生和脂膜是必不可少的。 营业额。在胎儿和出生后早期的大脑发育过程中，大脑中FA的合成对于快速 结构性脑发育。然而，脂肪酸也可以作为一种能量来源。最近的证据表明 神经干细胞和祖细胞在很大程度上依赖FA的氧化提供能量。问题是，余额是否 脑内FA合成和氧化(FA代谢)之间的关系在损伤后发生变化。新生儿脑损伤是一种 是长期神经发育迟缓的主要原因。对损伤的反应与内源性恢复 阶段的代谢成本很高，会带来额外的能量需求，并扰乱高度协调的 大脑发育和成熟的过程。因此，迫切需要划定急性和长期-- 新生儿脑损伤后的足月代谢适应。我们的初步结果显示，新生儿受伤 间歇性低氧导致大脑FA成分减少，增加了对FA作为燃料的依赖 与其他基质相比，增加了FA的氧化。此外，还增加了FA对氧化的动员 受伤后几天。基于这些结果，我们假设新生儿脑损伤后的代谢适应 直接扰乱脂肪酸合成和氧化的平衡，从而扰乱适时的发育轨迹 大脑的成长和成熟。我们将从三个方面检验我们的假设。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。这个目标将描绘出时间--和 海马区、白质区和脑室下区的区域特异性FA成分。特定地区 FAs和底物的组成将用串联质谱仪和MALDI-MS进行测量 光谱成像。我们将测量区域和细胞特定人群中的蛋白质、RNA和代谢流量。 将进行研究，以衡量使用FA和其他设备的依赖性、容量和灵活性 损伤后不同脑区、不同时间点的底物。在第二个目标中，我们将确定是否 祖细胞FA代谢的时间特异性改变扰乱了它们的正常发育轨迹。我们 将特异性地移除神经前体细胞中负责FA合成或氧化的专有基因，以 回答FA代谢是否调节神经源性壁龛中的神经前体细胞活动的问题。 在第三个目标中，我们将测试新生儿脑损伤后的脑FA氧化是适应性还是非适应性。 这一目的将利用PAN研究FA氧化在发育中的脑和新生儿脑损伤后的作用。 大脑特有的FA氧化专有基因或负责限速步骤的基因丢失 FA易位到线粒体。总体而言，这个项目将勾勒出FA的时间进程和贡献 朝向新陈代谢灵活性。这项研究的结果将为脂肪酸代谢科学提供参考和指导 旨在平衡新生儿脑损伤后代谢需求的新治疗靶点的开发。