Project II- Impact of Hypoxia-Ischemia and/or inflammation on Metabolism in Cerebellum

项目 II - 缺氧缺血和/或炎症对小脑代谢的影响

基本信息

批准号：
9979922
负责人：
MARY C MCKENNA
金额：
$ 25.65万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-17 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979922
关键词：
ATP Synthesis Pathway Acute Address Astrocytes Attenuated Brain Brain Hypoxia-Ischemia Brain Injuries Brain region Cardiolipins Ceftriaxone Cell Death Cell Nucleus Cell Respiration Cell physiology Cerebellar Nuclei Cerebellum Cerebral Palsy Cerebral cortex Childhood Choline Citric Acid Cycle Clinical Creatine Data Development Diagnosis Energy Metabolism Exhibits Failure Female Glucose Glutamates Glutamine Hippocampus (Brain)Hour Image Impairment Infant Inflammation Injury Inositol Lead Learning Lecithin Lipids Lysophospholipids Mass Spectrum Analysis Membrane Membrane Lipids Membrane Microdomains Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Motor Motor Skills Myelin N-acetylaspartate NADP NMR Spectroscopy Neurites Neurons Neurotransmitters Nucleotides Outcome Oxidation-Reduction Oxidative Stress Oxygen Pathway interactions Pentosephosphate Pathway Perinatal Hypoxia Pharmacotherapy Phosphocreatine Phospholipids Process Production Protein Biosynthesis Proteins Purkinje Cells Pyruvate Carboxylase Rattus Reduced Glutathione Reperfusion Therapy Signal Transduction Specificity Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Sphingomyelins Structure Taurine Techniques Testing Therapeutic behavioral outcome brain cell brain metabolism clinically relevant functional outcomes gamma-Aminobutyric Acid granule cell improved outcome insight lipid biosynthesis liquid chromatography mass spectrometry male membrane synthesis myelination natural hypothermia neonatal hypoxic-ischemic brain injury neonatal period neurotransmitter release novel perinatal injury postnatal protective effect pup response synaptogenesis white matter

ATP Synthesis Pathway Acute Address Astrocytes Attenuated Brain Brain Hypoxia-Ischemia Brain Injuries Brain region Cardiolipins Ceftriaxone Cell Death Cell Nucleus Cell Respiration Cell physiology Cerebellar Nuclei Cerebellum Cerebral Palsy Cerebral cortex Childhood Choline Citric Acid Cycle Clinical Creatine Data Development Diagnosis Energy Metabolism Exhibits Failure Female Glucose Glutamates Glutamine Hippocampus (Brain)Hour Image Impairment Infant Inflammation Injury Inositol Lead Learning Lecithin Lipids Lysophospholipids Mass Spectrum Analysis Membrane Membrane Lipids Membrane Microdomains Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Motor Motor Skills Myelin N-acetylaspartate NADP NMR Spectroscopy Neurites Neurons Neurotransmitters Nucleotides Outcome Oxidation-Reduction Oxidative Stress Oxygen Pathway interactions Pentosephosphate Pathway Perinatal Hypoxia Pharmacotherapy Phosphocreatine Phospholipids Process Production Protein Biosynthesis Proteins Purkinje Cells Pyruvate Carboxylase Rattus Reduced Glutathione Reperfusion Therapy Signal Transduction Specificity Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Sphingomyelins Structure Taurine Techniques Testing Therapeutic behavioral outcome brain cell brain metabolism clinically relevant functional outcomes gamma-Aminobutyric Acid granule cell improved outcome insight lipid biosynthesis liquid chromatography mass spectrometry male membrane synthesis myelination natural hypothermia neonatal hypoxic-ischemic brain injury neonatal period neurotransmitter release novel perinatal injury postnatal protective effect pup response synaptogenesis white matter

展开

项目摘要

Neonatal hypoxia-ischemia (H/I) leads to rapid energy failure in cortical, subcortical and hippocampal regions due to lack of oxygen and glucose delivery to brain. This is followed by a transient normalization during reperfusion and a later secondary energy failure (~2-6 hours after H/I) that ultimately leads to brain injury, and poor neurodevelopmental outcome. Inflammation occurring prior to H/I can exacerbate injury. Acute alterations in metabolism and prolonged metabolic dysregulation after neonatal H/I leave the brain vulnerable and unable to support processes essential for normal development. We will use a well-characterized model of perinatal H/I at term (postnatal (PN) day 10 rat pup) with and without prior inflammation. The effects of H/I on cerebellum have not been carefully explored even though the rapidly developing cerebellum is particularly vulnerable to inflammation and perinatal injury. We will combine high field 1H-NMR and 13C-NMR spectroscopy of energy metabolism and neurotransmitter synthesis with matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) determination of metabolites, lipids, proteins in specific layers of the cerebellum. Our studies will be the first determination of alterations in metabolism via astrocyte and neuron specific pathways and synthesis of glutamate and GABA in cerebellum after H/I. Molecular and metabolic alterations and long- term functional outcomes will determine the therapeutic potential of hypothermia and drug therapy. We hypothesize that neonatal H/I leads to energy failure in the cerebellum that contributes to impaired function of brain cells including acute and long-term alterations in energy metabolism and neurotransmitter synthesis. We hypothesize that the combined effect of inflammation and H/I exacerbates cerebellar damage and dysregulated metabolism in male and female brain. Our Specific Aims test these hypotheses: 1. Determine the effect of H/I at PN10 with and without prior inflammation on energy metabolism in cerebellum of male and female rat pups. 2. Determine the alterations in neurotransmitters, metabolites, lipids and proteins in Purkinje, molecular and granule cell layers, deep nuclei and white matter of the cerebellum of male and female pups after H/I with and without prior inflammation. 3. Determine the protective effect of hypothermia, choline and ceftriaxone alone, and these compounds in combination with hypothermia against changes in neuronal and glial metabolism and specific molecular changes in the Purkinje, molecular and granule cell layers, deep nuclei and myelin. Novel, clinically relevant information about the timing and targets of injury and alterations in neuron and astrocyte specific metabolic pathways in brain and alterations of metabolites, nucleotides, membrane and signaling lipids, and proteins in cerebellar layers and deep nuclei will be obtained using the unique combination of 1H- NMR and 13C-NMR in conjunction with MALDI-MSI and LC/MS-MS for profiling the changes after H/I with and without inflammation, inflammation alone and response to neuroprotective therapy.

新生儿缺氧 - 缺血（H/I）导致皮质，皮层和海马区域的快速能量失效由于缺乏氧气和葡萄糖递送到大脑。接下来是在再灌注和后来的继发能量衰竭（H/I后约2-6小时），最终导致脑损伤，并且神经发育结果差。 H/I之前发生的炎症会加剧损伤。急性改变在新生儿H/I后，新陈代谢和长期代谢失调使大脑脆弱，无法支持正常发展必不可少的过程。我们将使用围产期H/I的特征良好的模型在有和没有先前炎症的期限（出生后（PN）第10天小鼠）。 H/I对小脑的影响即使快速发展的小脑特别容易受到攻击，也没有仔细探索炎症和围产期损伤。我们将结合高场1H-NMR和13C-NMR能量光谱与基质辅助激光解吸/电离 - 质量光谱法合成代谢和神经递质的合成成像（MALDI-MSI）测定小脑特定层中代谢物，脂质，蛋白质的测定。我们的研究将是通过星形胶质细胞和神经元特定途径改变代谢改变的首次确定 H/I后小脑中谷氨酸和GABA的合成。分子和代谢改变以及长期项功能结果将确定体温过低和药物治疗的治疗潜力。我们假设新生儿H/I导致小脑的能量故障，这导致功能受损脑细胞包括能量代谢和神经递质合成的急性和长期改变。我们假设炎症和H/I的综合作用加剧了小脑损伤和失调男性和女性大脑的代谢。我们的具体目的测试以下假设：1。确定H/I的效果在pN10上，有和没有先前的炎症对男性和雌性大鼠幼犬小脑的能量代谢。 2。确定神经递质，代谢物，脂质和蛋白质的改变，分子和分子和 h/i之后的男性和雌性小脑的颗粒细胞层，深核和白质和白质没有事先炎症。 3。仅确定体温过低，胆碱和头孢曲松的保护作用，这些化合物与体温过低，反对神经元和神经胶质代谢的变化以及 Purkinje，分子和颗粒细胞层，深核和髓磷脂的特定分子变化。小说，有关神经元和星形胶质细胞损伤的时机和靶标的临床相关信息大脑中的特定代谢途径以及代谢物，核苷酸，膜和信号的变化脂质和小脑层中的蛋白质和深核将使用1H-的独特组合获得 NMR和13C-NMR与MALDI-MSI和LC/MS-MS结合使用，用于分析H/I之后的更改和没有炎症，单独炎症和对神经保护疗法的反应。