Increased persistent sodium current in SOD1 motoneurons

SOD1 运动神经元持续钠电流增加

基本信息

批准号：
7389591
负责人：
Charles Heckman
金额：
$ 31.44万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7389591
关键词：
Action Potentials Acute Address Affect Amyotrophic Lateral Sclerosis Animals Antidepressive Agents Behavior Binding Calcium Cell Death Cells Cessation of life Chronic Controlled Environment Coupled Cultured Cells Development Disease Disruption Drug Controls Embryo Fluorescent Antibody Technique GTP-Binding Proteins Glutamates Goals In Vitro Life Link Modeling Molecular Motor Neurons Mus Mutation Neuromodulator Neurotransmitters Norepinephrine Numbers Onset of illness Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Play Preparation Property Prozac Regulation Research Personnel Riluzole Role Serotonin Slice Sodium Staging Standards of Weights and Measures Symptoms Synapses System Therapeutic Time Transcriptional Activation Transgenic Organisms Up-Regulation Work density design excitotoxicity in vivo juvenile animal ligand gated channel monoamine mouse model mutant novel therapeutics programs response voltage voltage gated channel

项目摘要

DESCRIPTION (provided by applicant): One of the leading hypotheses for motoneuron degeneration in ALS is excitotoxicity, in which excessive calcium entry leads to cell death. Most work on excitotoxicity has focused on ligand-gated channels activated by the excitatory neurotransmitter glutamate. In contrast, this proposal focuses on the possibility that ALS alters voltage-gated channels and thus alters the intrinsic excitability of the motoneuron. We have shown that a specific type of sodium (Na+) channel is markedly elevated in motoneurons cultured from a transgenic mouse model of ALS (the SOD1 model). This current is NaP, the persistent component of the total Na+ current generating the action potential. NaP is a major factor controlling the number of action potentials per time generated in response to a given amount of synaptic input. Because each action potential allows calcium to enter the cell, elevated NaP in ALS motoneurons could play a major role in excitotoxic death. The goals of this proposal are to investigate mechanisms of the aberrant upregulation of NaP in mutant SOD1 motoneurons and to assess how drugs that change NaP influence motoneuron survival. Studies are carried out in culture, in vitro in a slice preparation, and in vivo in the intact animal, all using the mutant SOD1 mouse. Aim 1 considers the issue of whether molecular subtypes or densities of the Na channels themselves change. Aim 2 focuses on potential changes in the regulation of NaP in response to acute and chronic drug administration. The monoamines serotonin and norepinephrine enhance NaP and likely play a particularly important role in its normal regulation. In Aim 3, the effects of NaP-specific drugs studied in aim 2 are evaluated for their effect on motoneuron survival both in culture and in the intact mouse. A key question addressed by Aims 2 and 3 is whether the monoamines further increase NaP above its already high levels in mutant SOD1 motoneurons. If so, then standard anti-depressant drugs may actually exacerbate motoneuron degeneration. In Aim 4, we evaluate whether, as predicted from our cell culture work, NaP is upregulated at a very early stage in life. Presence of enhanced NaP in very young animals would indicate that this aberrant property may play a significant role in the disease onset. These studies will play an essential role in determining if NaP makes an important contribution to motoneuron degeneration in ALS. Moreover, the results may prove invaluable in establishing new therapeutic strategies

描述（由申请人提供）：ALS 运动神经元变性的主要假设之一是兴奋性毒性，其中过量的钙进入会导致细胞死亡。大多数关于兴奋性毒性的研究都集中在由兴奋性神经递质谷氨酸激活的配体门控通道上。相比之下，该提议关注的是 ALS 改变电压门控通道从而改变运动神经元内在兴奋性的可能性。我们已经证明，在 ALS 转基因小鼠模型（SOD1 模型）培养的运动神经元中，特定类型的钠 (Na+) 通道显着升高。该电流是 NaP，是产生动作电位的总 Na+ 电流的持续成分。 NaP 是控制响应给定量的突触输入而每次生成的动作电位数量的主要因素。由于每个动作电位都允许钙进入细胞，因此 ALS 运动神经元中 NaP 升高可能在兴奋性毒性死亡中发挥重要作用。该提案的目标是研究突变型 SOD1 运动神经元中 NaP 异常上调的机制，并评估改变 NaP 的药物如何影响运动神经元的存活。研究在培养物、体外切片制备物和体内完整动物中进行，全部使用突变型 SOD1 小鼠。目标 1 考虑 Na 通道本身的分子亚型或密度是否发生变化的问题。目标 2 重点关注 NaP 调节因急性和慢性给药而发生的潜在变化。单胺类血清素和去甲肾上腺素可增强 NaP，并可能在其正常调节中发挥特别重要的作用。在目标 3 中，评估了目标 2 中研究的 NaP 特异性药物对培养物和完整小鼠中运动神经元存活的影响。目标 2 和 3 解决的一个关键问题是单胺是否会进一步增加 NaP 至突变型 SOD1 运动神经元中已经很高的水平之上。如果是这样，那么标准抗抑郁药物实际上可能会加剧运动神经元变性。在目标 4 中，我们评估了 NaP 是否如我们的细胞培养工作所预测的那样在生命的早期阶段上调。在幼年动物中存在增强的 NaP 表明这种异常特性可能在疾病的发生中发挥重要作用。这些研究将在确定 NaP 是否对 ALS 运动神经元变性做出重要贡献方面发挥重要作用。此外，这些结果对于建立新的治疗策略可能具有无价的价值