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.

这种更新应用代表了一种高度协作的多学科方法，用于阐明由新生儿低氧/缺血/缺血（H/L）引起的损伤的分子机制，利用神经保护和神经源性干预措施，可以临床翻译。目标是（1）确定对发展中大脑的H/L损伤的机制，（2）确定复苏性高氧对损伤机制，神经发生和长期结局的影响，（3）在单独和组合临床上有效的干预措施，以及（4）在机构方面依赖性别依赖于GECENDER的临床差异。基于上一批赠款期间取得的进展以及新项目调查人员产生的结果，研究人员假设H/L损伤是由氧化应激之间的复杂相互作用，脂质RAFT蛋白质相互作用的破坏，急性线粒体后的代谢失败以及GABAergic刺激的衰减引起的。他们还假设，可以通过避免不必要的高氧，通过给予乙酰基--L-肉碱来刺激有氧能量代谢，通过抑制抑制和抑制性抑制性抑制抑制作用，来保护脂质后的氧化应激，可以通过乙酰L-carnitine抑制脂质后的脂质后，从而实现H/L的最佳神经保护，从而刺激有氧能量代谢加巴。项目I的重点是代谢衰竭和凋亡的线粒体机制，以及磺胺神经保护的分子基础。项目II侧重于神经元和神经胶质能代谢，神经递质生物合成以及通过乙酰基-L-肉碱神经保护的分子基础的早期和长期改变。研究包括串行体内成像，31p和1H-MR，以及Ex Vivo 13C-NMR光谱。 III项目的重点是神经发生，通过去极化GABA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侧重于H/L对Li细胞粘附分子的脂质筏蛋白相互作用和功能的影响，Li细胞粘附分子是一种参与神经突生长，神经元可塑性和信号转导途径的关键蛋白。所有项目将使用核心B支持的新生儿大鼠H/L模型，以及在体外发育的不同阶段使用培养的皮质或海马神经元的常见O2和葡萄糖剥夺模型。所有项目还与氧化应激的共同主题，性别对机制和结果的影响以及通过防御细胞死亡，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）

Small, membrane-bound, alternatively spliced forms of ankyrin 1 associated with the sarcoplasmic reticulum of mammalian skeletal muscle.

DOI：
10.1083/jcb.136.3.621
发表时间：
1997-02-10
期刊：
The Journal of cell biology
影响因子：
0
作者：
Zhou D;Birkenmeier CS;Williams MW;Sharp JJ;Barker JE;Bloch RJ
通讯作者：
Bloch RJ

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.

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。