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: 10539030
• 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/10539030
• 关键词: Acute; Address; 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 (Brain); Histologic; Hypoxia; Image; Impairment; Injury; Knowledge; Lead; 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; Preterm brain injury; Process; Production; 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; base; behavioral study; brain metabolism; density; dietary; experience; fatty acid metabolism; fatty acid oxidation; fetal; flexibility; functional outcomes; improved; inflammatory marker; mass spectrometric imaging; migration; myelination; neonatal period; nerve stem cell; 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）在发育中的大脑中至关重 周转。在胎儿和早期出生后大脑发育期间，大脑中的FA合成对于快速 结构性大脑生长。但是，FAS也可以用作能源。最近的证据表明 神经茎和祖细胞在很大程度上依赖于FA氧化的能量。问题是平衡是否 损伤后大脑中的FA合成与氧化（FA代谢）之间。新生儿脑损伤是 长期神经发育延迟的主要贡献者。对伤害和内源性恢复的反应 阶段在代谢上昂贵，施加了额外的能源需求并破坏了高度精心策划的 大脑发育和成熟过程。因此，迫切需要描绘急性和长期 新生儿脑损伤后的术语代谢适应。我们的初步结果表明新生儿受伤 间歇性缺氧的大脑减少了FA组成，增加对FA的依赖性作为燃料 与其他底物和FA氧化增加相比。另外，FA动员氧化增加了 受伤几天。基于这些结果，我们假设新生儿脑损伤后代谢适应 直接扰动FA合成和氧化的平衡，从而破坏了及时的发展轨迹 大脑生长和成熟。我们将以三个目标来检验我们的假设。在第一个目标中，我们将确定 新生儿脑损伤后FA代谢的时间和空间贡献。这个目标将描绘时间和 海马，白质和室内区域中的区域特异性FA组成。特定区域 Fas和底物的组成将通过串联质谱法和马尔特群进行测量 光谱成像。我们将测量区域和细胞特异性种群中的蛋白质，RNA和代谢通量。 将进行研究，以衡量利用FAS和其他的依赖性，能力和灵活性 受伤后不同大脑区域和时间点的底物。在第二个目标中，我们将确定是否 祖细胞中FA代谢的时间特异性改变会破坏其正常发育轨迹。我们 将特别删除负责FA合成或神经祖细胞中FA合成或氧化的强制性基因 回答FA代谢是否调节神经源性壁ches中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氧化是适应性或适应不良的。 该目标将研究FA氧化在发育中的大脑和新生儿脑损伤后使用pan- 大脑特异性损失是FA氧化中的强制基因或负责限速步骤的基因 FA转移到线粒体中。总体而言，该项目将描述FAS的时间和贡献 迈向代谢灵活性。这项研究的结果将为FA代谢科学提供信息和指南 新的治疗靶标的发展旨在平衡新生儿脑损伤后代谢需求。