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Metabolic & Developmental Aspects of Intellectual Disability

新陈代谢

基本信息

批准号：
8230581
负责人：
MARY C MCKENNA
金额：
$ 96.13万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-05-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8230581
关键词：
Acute Acute Brain Injuries Address Aerobic Apoptosis Astrocytes Biochemical Brain Brain Hypoxia-Ischemia Brain Injuries Cell Adhesion Molecules Cell Death Cell membrane Child Complement Complex Data Development Energy Metabolism Estradiol Event Failure Functional disorder Funding Gender Genomics Glucose Goals Grant Hippocampus (Brain)Human Resources Hyperoxia Hypoxia Image Impairment In Vitro Inhibition of Apoptosis Injury Intellectual functioning disability Intervention Ischemia Ketone Bodies Knowledge Laboratories Lead Learning Levocarnitine Acetyl Lipids Membrane Microdomains Mental Retardation Metabolic Metabolism Mitochondria Mitochondrial Proteins Modeling Molecular NMR Spectroscopy Neonatal Neonatal Brain Injury Nerve Degeneration Neuraxis Neurites Neurologic Neurological outcome Neuronal Plasticity Neurons Neurotransmitters Outcome Oxidative Stress Play Predisposition Process Proteins Rattus Recording of previous events Regulation Research Research Personnel Respiration Retirement Role Signal Transduction Signal Transduction Pathway Site Source Staging Sulforaphane Therapeutic Translating Withdrawal attenuation base brain metabolism clinically relevant conditioning deprivation design effective intervention gamma-Aminobutyric Acid in vivo interdisciplinary approach medical schools mitochondrial dysfunction neonate neurogenesis neuron loss neuronal survival neuroprotection neurotransmitter biosynthesis novel therapeutic intervention programs response trafficking

项目摘要

This renewal application represents a highly collaborative, multidisciplinary approach to elucidate molecular mechanisms of injury to the immature brain caused by neonatal hypoxic/ischemia (H/l), utilizing neuroprotective and neurogenic interventions that can be clinically translated. The goals are to (1) identify mechanisms of H/l injury to the developing brain, (2) identify the effects of resuscitative hyperoxia on injury mechanisms, neurogenesis, and long-term outcome, (3) develop clinically-realistic interventions that are effective both alone and in combination, and (4) characterize gender-dependent differences in mechanisms and responses to intervention. Based on progress made during the previous grant period and on results generated by the new project investigators, the investigators hypothesize that H/l injury is caused by complex interactions among oxidative stress, disruption of lipid raft-protein interactions, metabolic failure subsequent to acute mitochondrial injury, and attenuation of GABAergic stimulation. They also hypothesize that optimal neuroprotection following H/l can be achieved by avoiding unnecessary hyperoxia, stimulating aerobic energy metabolism by administration of acetyl-L-carnitine, protecting lipid rafts, genomic post-conditioning against secondary oxidative stress by administration of sulforaphane, and inhibition of apoptosis and stimulation of neurogenesis by administration of estradiol and enhancement of GABA. Project I focuses on mitochondrial mechanisms of metabolic failure and apoptosis, and on the molecular basis for neuroprotection by sulforaphane. Project II focuses on early and long-term alterations in neuronal and glial energy metabolism, neurotransmitter biosynthesis, and the molecular basis for neuroprotection by acetyl-L-carnitine. Studies include serial in vivo imaging, 31P and 1H-MR, and ex vivo 13C-NMR spectroscopy. Project III focuses on neurogenesis, its regulation by depolarizing GABA, and how estradiol can promote neurogenesis and neuronal survival. Project IV focuses on the effects of H/l on lipid raft-protein interactions and function of the LI cell adhesion molecule, a key protein involved in neurite outgrowth, neuronal plasticity, and signal transduction pathways. All projects will use the neonatal rat H/l model, supported by Core B, and a common O2 and glucose deprivation model using cultured cortical or hippocampal neurons at different stages of in vitro development. All projects are also tied together by the common theme of oxidative stress, the effects of gender on mechanisms and outcome, as well as optimization of neurologic outcome by protection against cell death, protecting mitochondrial proteins, preserving signal transduction, or promotion of neurogenesis.

该更新申请代表了一种高度协作的多学科方法，用于阐明新生儿缺氧/缺血（H/I）引起的未成熟大脑损伤的分子机制，利用可以临床转化的神经保护和神经源性干预。目的是（1）确定H/I损伤对发育中大脑的机制，（2）确定复苏性高氧对损伤机制、神经发生和长期结局的影响，（3）开发单独和联合有效的临床现实干预措施，以及（4）表征机制和干预反应的性别依赖性差异。基于在前一个资助期间取得的进展和新项目研究者产生的结果，研究者假设H/I损伤是由氧化应激、脂筏-蛋白质相互作用的破坏、急性线粒体损伤后的代谢衰竭和GABA能刺激的减弱之间的复杂相互作用引起的。他们还假设，H/I后的最佳神经保护可以通过避免不必要的高氧、通过施用乙酰-L-肉毒碱刺激有氧能量代谢、保护脂筏、通过施用萝卜硫素抵抗继发性氧化应激的基因组后调节、以及通过施用雌二醇和增强GABA抑制细胞凋亡和刺激神经发生来实现。项目一的重点是线粒体代谢失败和细胞凋亡的机制，并在萝卜硫素神经保护的分子基础。项目II的重点是早期和长期的神经元和神经胶质细胞的能量代谢，神经递质的生物合成，乙酰左旋肉碱的神经保护的分子基础的改变。研究包括系列体内成像、31 P和1H-MR以及离体13 C-NMR光谱。项目III的重点是神经发生，其调节去极化GABA，以及如何雌二醇可以促进神经发生和神经元存活。项目IV的重点是H/L对脂筏-蛋白质相互作用和LI细胞粘附分子功能的影响，LI细胞粘附分子是参与神经突生长、神经元可塑性和信号转导途径的关键蛋白。所有项目都将使用由核心B支持的新生大鼠H/I模型，以及使用体外发育不同阶段的培养皮层或海马神经元的常见O2和葡萄糖剥夺模型。所有项目也通过氧化应激的共同主题联系在一起，性别对机制和结果的影响，以及通过保护细胞死亡，保护线粒体蛋白，保护信号转导或促进神经发生来优化神经学结果。