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 (FA) 对于大脑发育中的髓鞘形成、神经发生和脂质膜至关重要 周转。在胎儿和出生后早期大脑发育期间，大脑中的 FA 合成对于快速 大脑的结构性生长。然而，FA 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靠 FA 氧化来获取能量。问题是是否平衡 受伤后大脑中 FA 合成和氧化（FA 代谢）之间的变化。新生儿脑损伤是一种 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 这个阶段的代谢成本很高，会产生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，迫切需要区分急性和长期的症状。 新生儿脑损伤后的足月代谢适应。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 的组成，增加了对 FA 作为燃料的依赖 与其他底物相比，FA 氧化增加。此外，FA 的氧化动员也增加 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FA合成和氧化的平衡，从而扰乱及时的发育轨迹 大脑的生长和成熟。我们将在三个目标上检验我们的假设。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。这一目标将划定时间和 海马、白质和室下区区域特异性 FA 组成。特定地区的 FA 和底物的组成将通过串联质谱法和 MALDI-mass 进行测量 光谱成像。我们将测量特定区域和细胞群体中的蛋白质、RNA 和代谢通量。 将进行研究来衡量利用 FA 和其他方法的依赖性、能力和灵活性 来自不同大脑区域和受伤后时间点的底物。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扰乱其正常发育轨迹。我们 将专门去除神经祖细胞中负责 FA 合成或氧化的专性基因 回答 FA 代谢是否调节神经源性微环境中的神经祖细胞活性的问题。 第三个目标是，我们将测试新生儿脑损伤后脑 FA 氧化是适应性还是适应不良。 这一目标将利用泛素研究 FA 氧化在发育中的大脑和新生儿脑损伤后的作用。 FA 氧化中的专性基因或负责 FA 氧化限速步骤的基因的脑特异性丢失 FA 易位至线粒体。总体而言，该项目将描述 FA 的时间进程和贡献 迈向代谢灵活性。这项研究的结果将为 FA 代谢科学提供信息并指导 开发新的治疗靶点，旨在平衡新生儿脑损伤后的代谢需求。