Identifying excitotoxic mechanisms in a C. elegans model of axon destabilization

识别线虫轴突不稳定模型中的兴奋性毒性机制

• 批准号: 8203155
• 负责人: Belinda Barbagallo
• 金额: $ 2.83万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8203155
• 关键词: Amyotrophic Lateral Sclerosis; Attenuated; Axon; Biological Models; Caenorhabditis elegans; Calcium; Calcium Channel; Cell Death; Cessation of life; Data; Disease; Goals; Homeostasis; Human; Human Pathology; Ion Channel; Ischemic Stroke; Mediating; Modeling; Molecular; Motor; Motor Neuron Disease; Motor Neurons; Muscle; Nematoda; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Organism; Play; Prevention; Process; Publishing; Reporting; Role; Route; Sclerosis; Stroke; Structure; Symptoms; Synapses; System; Testing; Toxic effect; Work; axonal degeneration; cell injury; excitotoxicity; genetic manipulation; mutant; neuron loss; neuronal cell body; neurotoxicity; prevent; receptor; research study; voltage

DESCRIPTION (provided by applicant): Excess ion channel activation can have devastating consequences for the nervous system, often resulting in cell death. Excitotoxic or ion-channel mediated cell death is a major cause of the debilitating loss of neurons that occurs during pathological conditions such as ischemic stroke1, and is also a contributing factor in a variety of human neurodegenerative diseases including amyotrophic lateral sclerosis (ALS)2. Preliminary work on a Caenorhabditis elegans model of excitotoxicity shows that in cases where cell body death is prevented, axonal destabilization still occurs3. The goal of this proposal is to identify the mechanisms underlying synaptic decoupling and altered calcium homeostasis in axons, which occur during excitotoxic cell damage. In Aim 1, I will test the hypothesis that axonal destabilization is mediated through increased calcium stores and requires both voltage gated and ER localized channel receptors. In Aim 2, I will identify the role of calcium in axon destabilization and implicate specific classes of calcium channels in mediating the accumulation of toxic levels of calcium in axons. PUBLIC HEALTH RELEVANCE: Excitotoxicity occurs as a result of many prevalent human pathologies, such as stroke and amyotrophic later sclerosis (ALS). The work proposed will identify the mechanisms that are responsible for mediating excitotoxic cell death. The mechanisms of cell death in axons can be used as targets for the treatment and prevention of axon loss in neurodegenerative diseases.

描述（由申请人提供）：过量的离子通道激活可能会对神经系统产生毁灭性后果，通常导致细胞死亡。兴奋性毒性或离子通道介导的细胞死亡是在病理状况（例如缺血性stroke1）中导致神经元丧失的主要原因，也是包括各种人类神经退行性疾病在内的多种因素，包括肌萎缩性侧面硬化症（ALS）2。秀丽隐杆线虫模型的兴奋性毒性模型的初步工作表明，在预防细胞体死亡的情况下，轴突不稳定仍会发生3。该提案的目的是确定突触突触解耦的基础机制，并改变轴突中钙稳态的改变，这些机制在兴奋性细胞损伤期间发生。在AIM 1中，我将测试以下假设：轴突不稳定是通过增加的钙存储介导的，并且需要电压门控和ER局部通道受体。在AIM 2中，我将确定钙在轴突不稳定中的作用，并暗示钙通道的特定类别在介导轴突中钙的毒性水平的积累中。 公共卫生相关性：兴奋性毒性是由于许多普遍的人类病理，例如中风和肌萎缩性后来的硬化症（ALS）。提出的工作将确定负责介导兴奋性细胞死亡的机制。轴突中细胞死亡的机制可用作治疗和预防神经退行性疾病中轴突损失的靶标。