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：
7796818
负责人：
ELIAS K MICHAELIS
金额：
$ 27.42万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7796818
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 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 Tyrosine Kinase Proteins 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 animal model development 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 overexpression oxidation programs promoter protein complex 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谷氨酸 (Glu) 释放和积累的增加神经元的细胞外空间。与年龄相关的细胞外谷氨酸增加是由于部分丧失谷氨酸转运蛋白的活性。基本上中枢神经系统 (CNS) 中的所有神经元都暴露于细胞外谷氨酸升高，但并非所有大脑区域都受到同样的影响。某些神经元对通过 Ca2+- 和氧化应激介导的过程产生的 Glu 的毒性作用随着年龄的增长而增加。某些神经元对谷氨酸的不同脆弱性的原因仍不清楚。另外，没有动物模型中枢神经系统中与年龄相关的谷氨酸释放增加可用于确定过量的谷氨酸如何产生其对老化神经元的影响。我们已经培育出转基因 (Tg) 小鼠，它们具有额外的 Glu 基因拷贝脱氢酶 1 (GLUD1)，一种线粒体酶，被认为是生物合成中的限速步骤 Glu 作为递质。在神经元特异性启动子的控制下引入的 GLUD1 转基因是仅在神经元中表达。 GLUD1 小鼠比野生小鼠具有更高水平的去极化诱导的 Glu 释放类型（wt）并在特定神经元群体中遭受损失。 GLUD1小鼠的寿命也会缩短没有表现出严重的神经功能障碍。正在检验的假设是过量的细胞外衰老大脑中的谷氨酸会引发导致中枢神经系统代谢状态改变的事件，对特定人群造成损害神经元的数量、损伤与恢复之间的不平衡、周围组织的代谢应激，以及寿命缩短。短期目标是： a) 量化寿命和蛋白质/DNA 的变化高谷氨酸能小鼠和野生型小鼠的大脑和其他组织中的氧化； b) 确定变化脆弱和抵抗神经元的代谢、基因表达和形态； c) 表征信号蛋白复合物参与主动神经突重塑，并定义谷氨酸过度活跃和衰老的机制影响这个复合体。长期目标是了解分子和细胞过程中枢神经系统中谷氨酸活性的增加与神经元结构和功能的年龄依赖性变化有关，但没有神经系统疾病，并确定治疗干预的潜在目标。为了检验假设，我们制定了以下具体目标：1) 评估寿命以及大脑中蛋白质和 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的作用过度表达和衰老对弱势群体和群体的结构、代谢和基因表达变化的影响抵抗神经元； 3) 确定年龄相关的表达、组成和活性的变化 GLUD1 和 wt 小鼠中的 Ca2+ 敏感、树突生长控制复合物。这些研究利用了与年龄相关的高谷氨酸能状态的新型动物模型，以探讨差异机制神经元脆弱性和神经元从应激中恢复的新分子机制。