GLUTAMATE NEUROTRANSMISSION, AGING, LONGEVITY AND NEURITE REMODELING

谷氨酸神经传递、衰老、长寿和神经突重塑

基本信息

批准号：
7347340
负责人：
ELIAS K MICHAELIS
金额：
$ 27.62万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7347340
关键词：
3-nitrotyrosine Actins Affect Age Aging Agonist Anabolism Animal Model Axon Behavioral Brain Brain Injuries Brain region Caloric Restriction Cell physiology Characteristics Collaborations Complex D Aspartate DNA Dendrites Deoxyguanosine Development Diet Elderly Enzymes Event Exhibits Extracellular Space Gene Expression Generations Genes Glutamate Dehydrogenase Glutamate Receptor Glutamate Transporter Glutamates Green Fluorescent Proteins Growth Hippocampus (Brain)Human Hyperactive behavior Injury Kidney Knock-out Lasers Lead Learning Link Liver Longevity Maintenance Mammals Measures Mediating Membrane Memory Memory impairment Metabolic Metabolic stress Metabolism Mitochondria Modeling Molecular Morphology Mus N-Methylaspartate Nerve Nervous System Trauma Neuraxis Neurites Neurologic Neurologic Dysfunctions Neuron-Specific Enolase Neurons Oxidative Stress Oxidoreductase Pathway interactions Peripheral Pharmaceutical Preparations Phosphatidylinositol Transfer Protein Phosphorylation Population Principal Investigator Process Production Proline Protein Overexpression Protein Tyrosine Kinase Proteins Rate Reactive Oxygen Species Recovery Recovery of Function Research Resistance Rodent Signal Transduction Signaling Protein Skeletal Muscle Somatosensory Cortex Stress Structure Testing Therapeutic Intervention Tissues Toxic effect Transgenes Transgenic Mice Transgenic Organisms Wild Type Mouse age effect age related aged aging brain analog base cytotoxic density extracellular fly frontal lobe hippocampal pyramidal neuron innovation juvenile animal mRNA Expression middle age nervous system disorder neurite growth neurochemistry neuron loss neuronal survival neurotransmission novel oxidation programs promoter somatosensory

项目摘要

An important aspect of brain aging is the increased glutamate (Glu) release and accumulation in the extracellular space of neurons. Age-associated increases in extracellular Glu occur because of partial loss of activity of Glu transporters. Essentially all neurons in the central nervous system (CNS) are exposed to elevated extracellular Glu, yet not all brain regions suffer equally. The sensitivity of certain neurons to the toxic effects of Glu produced through Ca2+- and oxidative stress-mediated processes, increases with age. The reasons for differential vulnerability of certain neurons to Glu are still not known. Also, no animal model of age-associated increases in Glu release in CNS is available to determine how excess Glu produces its effect on aging neurons. We have generated transgenic (Tg) mice that have extra copies of the gene for Glu dehydrogenase 1 (GLUD1), a mitochondrial enzyme considered to be a rate-limiting, step in the biosynthesis of Glu as a transmitter. The GLUD1 transgene, introduced under the control of a neuron-specific promoter, is expressed only in neurons. GLUD1 mice have higher levels of depolarization-induced Glu release than wild type (wt) and suffer losses in specific neuronal populations. GLUD1 mice also have a shortened life span without exhibiting severe neurological dysfunction. The hypothesis being tested is that excess extracellular Glu in aging brain initiates events that lead to altered metabolic states in CNS, damage to select populations of neurons, an imbalance between damage and recovery, metabolic stress in peripheral tissues, and decreased longevity. Short-term objectives are: a) To quantify changes in longevity and protein/ DNA oxidation in brain and other tissues of hyper-glutamatergic and wt mice; b) To determine changes in metabolism, gene expression, and morphology of vulnerable and resistant neurons; and c) To characterize a signaling protein complex involved in active neurite remodeling and define how Glu hyperactivity and aging affect this complex. The long-term objectives are to understand the molecular and cellular processes that link increased Glu activity in CNS to age-dependent changes in neuronal structure and function, but without neurological disease, and to identify potential targets for therapeutic intervention. To test the hypothesis, we developed the following specific aims: 1) Assess longevity and protein and DNA oxidation levels in brain and other tissues of wt and Tg mice during aging; 2) Determine the effects of neuronal GLUD1 overexpression and of aging on structural, metabolic and gene expression changes in vulnerable and resistant neurons; and 3) Determine the age-dependent changes in expression, composition and activity of a Ca2+-sensitive, dendrite-growth controlling complex in GLUD1 and wt mice. These studies make use of a novel animal model of age-associated hyperglutamatergic states to probe mechanisms of differential neuronal vulnerability and novel molecular mechanisms of neuronal recovery from stress.

大脑衰老的一个重要方面是增加谷氨酸（GLU）释放和积累神经元的细胞外空间。由于年龄相关的细胞外GLU增加，由于部分损失 GLU转运蛋白的活性。本质上，中枢神经系统（CNS）中的所有神经元都暴露于升高的细胞外GLU，但并非所有大脑区域都遭受平常的影响。某些神经元对通过Ca2+产生的GLU的毒性作用以及氧化应激介导的过程，随着年龄的增长而增加。某些神经元对GLU的差异脆弱性的原因尚不清楚。另外，没有动物模型 CNS中GLU释放的年龄相关增长可用于确定多余的GLU如何产生其对衰老神经元的影响。我们已经产生了具有额外基因GLU副本的转基因（TG）小鼠脱氢酶1（GLUD1），一种线粒体酶，被认为是速率限制的，在生物合成中逐步 Glu作为发射机。在神经元特异性启动子控制下引入的GLUD1转基因是仅在神经元中表达。 GLUD1小鼠比野生具有更高水平的去极化诱导的GLU释放类型（WT）并在特定神经元种群中遭受损失。 GLUD1小鼠的寿命也缩短没有表现出严重的神经功能障碍。测试的假设是细胞外过多衰老大脑中的GLU会引发导致CNS代谢状态变化的事件，对选择人群的损害神经元，损伤与恢复之间的失衡，周围组织中的代谢应激以及寿命降低。短期目标是：a）量化寿命和蛋白质/ DNA的变化高谷氨酸能和WT小鼠的大脑和其他组织中的氧化； b）确定变化脆弱和抗性神经元的代谢，基因表达和形态； c）表征一个信号传导蛋白复合物参与活性神经突重塑并定义GLU多动症和衰老如何影响这个复合物。长期目标是了解分子和细胞过程将CN中的GLU活性增加与神经元结构和功能的年龄依赖性变化，但没有神经疾病，并确定治疗干预的潜在靶标。为了检验假设，我们开发了以下特定目的：1）评估大脑中的寿命和蛋白质和DNA氧化水平以及衰老期间WT和TG小鼠的其他组织； 2）确定神经元GLUD1的影响过表达以及易受伤害的结构，代谢和基因表达变化的衰老抗性神经元； 3）确定A表达，组成和活性的年龄依赖性变化 Ca2+ - 敏感，树突生长控制glud1和WT小鼠中的复合物。这些研究利用了与年龄相关的高谷氨酸能态的新型动物模型，以探测差异机制神经元脆弱性和新型分子机制从压力中恢复。