Metabolic & Developmental Aspects of Intellectual Disability

新陈代谢

基本信息

批准号：
8438433
负责人：
MARY C MCKENNA
金额：
$ 91.6万
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 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8438433
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.

这一更新应用代表了一种高度协作、多学科的方法，利用可临床转化的神经保护和神经源性干预措施，阐明新生儿缺氧/缺血 (H/l) 引起的未成熟大脑损伤的分子机制。目标是 (1) 确定 H/l 对发育中大脑损伤的机制，(2) 确定复苏性高氧对损伤机制、神经发生和长期结果的影响，(3) 制定临床现实的干预措施单独和组合均有效，(4) 描述机制和干预反应中性别依赖性差异的特征。根据先前资助期间取得的进展以及新项目研究人员产生的结果，研究人员假设 H/l 损伤是由氧化应激、脂筏-蛋白质相互作用破坏、急性线粒体继发代谢衰竭之间复杂的相互作用引起的。损伤和 GABA 能刺激的减弱。他们还假设，H/l 后的最佳神经保护可以通过以下方式实现：避免不必要的高氧、通过施用乙酰基-L-肉碱刺激有氧能量代谢、保护脂筏、通过施用萝卜硫素针对继发性氧化应激进行基因组后调节以及抑制通过施用雌二醇和增强 GABA 来抑制细胞凋亡和刺激神经发生。项目 I 重点研究代谢衰竭和细胞凋亡的线粒体机制，以及萝卜硫素神经保护的分子基础。项目 II 重点关注神经元和神经胶质能量代谢、神经递质生物合成以及乙酰左旋肉碱神经保护的分子基础的早期和长期改变。研究包括连续体内成像、31P 和 1H-MR 以及离体 13C-NMR 光谱。项目 III 重点关注神经发生、GABA 去极化的调节，以及雌二醇如何促进神经发生和神经元存活。项目 IV 重点研究 H/l 对脂筏-蛋白相互作用和 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 Core B 支持的新生大鼠 H/l 模型，以及使用处于体外发育不同阶段的培养皮质或海马神经元的常见 O2 和葡萄糖剥夺模型。所有项目还通过以下共同主题联系在一起：氧化应激、性别对机制和结果的影响，以及通过防止细胞死亡、保护线粒体蛋白、保留信号转导或促进神经发生来优化神经系统结果。

项目成果

期刊论文数量（121）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Functional intracellular glutaminase activity in intact astrocytes.

完整星形胶质细胞中功能性细胞内谷氨酰胺酶活性。

DOI：
10.1007/bf01000035
发表时间：
1989
期刊：
Neurochemical research
影响因子：
4.4
作者：
Zielke,HR;Tildon,JT;Zielke,CL;Baab,PJ;Landry,ME
通讯作者：
Landry,ME

Substrate oxidation by isolated rat brain mitochondria and synaptosomes.

分离的大鼠脑线粒体和突触体的底物氧化。

DOI：
10.1002/jnr.490140206
发表时间：
1985
期刊：
Journal of neuroscience research
影响因子：
4.2
作者：
Tildon,JT;Roeder,LM;Stevenson,JH
通讯作者：
Stevenson,JH

In vivo longitudinal proton magnetic resonance spectroscopy on neonatal hypoxic-ischemic rat brain injury: Neuroprotective effects of acetyl-L-carnitine.

DOI：
10.1002/mrm.25537
发表时间：
2015-12
期刊：
MAGNETIC RESONANCE IN MEDICINE
影响因子：
3.3
作者：
Xu, Su;Waddell, Jaylyn;Zhu, Wenjun;Shi, Da;Marshall, Andrew D.;McKenna, Mary C.;Gullapalli, Rao P.
通讯作者：
Gullapalli, Rao P.

Muscarinic receptor binding and oxidative enzyme activities in the adult rat superior cervical ganglion: effects of 6-hydroxydopamine and nerve growth factor.

成年大鼠颈上神经节毒蕈碱受体结合和氧化酶活性：6-羟基多巴胺和神经生长因子的影响。

DOI：
10.1523/jneurosci.03-10-01963.1983
发表时间：
1983
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Dombrowski,AM;Jerkins,AA;Kauffman,FC
通讯作者：
Kauffman,FC

Mode of death effect on rat liver iodothyronine 5' deiodinase activity: role of adenosine 3',5' monophosphate.

死亡方式对大鼠肝脏碘甲状腺原氨酸5脱碘酶活性的影响：腺苷3,5单磷酸的作用。