Gpx4 and ferroptosis inhibition in retarding ALS

Gpx4 和铁死亡抑制可延缓 ALS

• 批准号: 9898290
• 负责人: QITAO RAN
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898290
• 关键词: Ablation; Affect; Amyotrophic Lateral Sclerosis; Apoptosis; Attenuated; Biochemistry; Brain region; Cell Death; Cells; Cerebral cortex; Cessation of life; Data; Degenerative Disorder; Dependovirus; Development; Disease; Disease Progression; Exhibits; Genetic; Hydrogen Peroxide; Induced Mutation; Intervention; Iron; Journals; Lead; Lipid Peroxidation; Longevity; Mediating; Membrane; Membrane Lipids; Military Personnel; Mitochondria; Motor Neurons; Mus; Nerve Degeneration; Neurons; Onset of illness; Paper; Paralysed; Pathologic; Phenotype; Publishing; Respiratory Failure; Risk; Role; Services; Spinal; Spinal Cord; Symptoms; Tamoxifen; Testing; Transgenic Organisms; Veterans; Viral; design; effective therapy; effectiveness evaluation; experimental study; gene therapy; glutathione peroxidase; improved; inhibitor/antagonist; insight; motor neuron degeneration; mouse model; neuron loss; novel; novel therapeutic intervention; overexpression; oxidative damage; selenoprotein; therapeutic evaluation

Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron degenerative disease, in which motor neuron degeneration and death result in progressive paralysis and eventual death by respiratory failure. ALS is a particular concern for veterans as several studies indicated that military service is associated with increased risk of ALS. At present, there are no effective treatments for this debilitating disease and the development of effective therapies is impeded by the lack of suitable targets, particularly for sporadic ALS, which represents the majority cases that do not have identifiable genetic causes. Glutathione peroxidase 4 (Gpx4) is a selenoprotein glutathione peroxidase important in protecting membranes against oxidative damage. Recently, Gpx4 was identified as a key inhibitor of ferroptosis, an oxidative, iron- dependent cell death mechanism different from other cell death mechanisms such as apoptosis. Serendipitously, we discovered that Gpx4 is a key protector of spinal motor neurons. In addition, our preliminary results indicated that overexpression of Gpx4 extended lifespan of ALS mice. Our preliminary results further suggested that the ferroptosis inhibition function of Gpx4 is important for motor neuron protection. Built upon these exciting results, this project is designed to test the therapeutic potential of Gpx4 overexpression and ferroptosis inhibition for ALS. The overall hypothesis to be tested in this project is: Gpx4 overexpression and ferroptosis inhibition can ameliorate motor neuron degeneration and retard disease of ALS. The hypothesis will be tested by three specific aims. Aim 1 is to determine whether Gpx4 overexpression improves locomotor function and attenuates motor neuron degeneration in ALS mice. Aim 2 is to examine the role of ferroptosis inhibition in retarding disease in ALS mice. Aim 3 is to determine the effect of Gpx4 overexpression mediated by viral delivery in retarding disease of ALS mice. The results from this project will provide novel insights into the mechanism of motor neuron degeneration in ALS, and importantly, could lead to new therapeutic strategies for ALS.

肌萎缩侧索硬化症(ALS)是最常见的运动神经元变性 运动神经元变性和死亡导致进行性瘫痪和 最终死于呼吸衰竭。肌萎缩侧索硬化症是退伍军人特别关注的问题，有几项研究 指出服兵役与肌萎缩侧索硬化症的风险增加有关。目前，还没有 这种使人衰弱的疾病的有效治疗方法和有效疗法的开发是 由于缺乏合适的目标，特别是对于零星的ALS，这代表着 大多数病例没有可识别的遗传原因。谷胱甘肽过氧化物酶4(Gpx4)是一种 硒蛋白谷胱甘肽过氧化物酶在保护膜免受氧化中的重要作用 损坏。最近，Gpx4被确定为铁下垂的关键抑制剂，铁下垂是一种氧化性的铁- 依赖性细胞死亡机制不同于其他细胞死亡机制，如细胞凋亡。 偶然的是，我们发现Gpx4是脊髓运动神经元的关键保护者。此外, 我们的初步结果表明，过表达Gpx4可以延长ALS小鼠的寿命。我们的 初步结果进一步表明Gpx4的铁性下垂抑制功能是重要的。 用于运动神经元保护。在这些令人兴奋的结果的基础上，该项目旨在测试 Gpx4过表达和铁下垂抑制对ALS的治疗潜力。整体而言 本项目要检验的假设是：Gpx4的过度表达和下垂的抑制可以 改善肌萎缩侧索硬化症运动神经元变性，延缓疾病进展。这一假设将得到检验。 通过三个具体的目标。目的1是确定Gpx4过度表达是否能改善运动能力 对ALS小鼠运动神经元变性有一定的保护作用。目标2是考察 抑制肌萎缩侧索硬化症小鼠的铁性下垂。目的3是确定Gpx4的作用 病毒介导的过表达在ALS小鼠延缓疾病中的作用。由此产生的结果是 该项目将为肌萎缩侧索硬化症运动神经元变性的机制提供新的见解，以及 重要的是，这可能会导致ALS的新治疗策略。