Investigation of Ferroptosis as a Therapeutic Target for ALS

铁死亡作为 ALS 治疗靶点的研究

• 批准号: 10588525
• 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: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588525
• 关键词: Ablation; Acceleration; Affect; Amyotrophic Lateral Sclerosis; Apoptosis; Astrocytes; Cell Death; Cells; Cessation of life; Degenerative Disorder; Disease; Effectiveness; Intervention; Investigation; Iron; Life; Longevity; Modality; Motor Neuron Disease; Motor Neurons; Mus; Neuroglia; Neurons; Onset of illness; Paralysed; Pathogenesis; Production; Reporting; Research; Risk; Role; Spinal; Stress; Symptoms; Syndrome; System; Testing; Therapeutic; Tissues; Uterus; Vertebral column; Veterans; cell type; cohort; efficacious treatment; efficacy evaluation; efficacy testing; glutathione peroxidase; improved; in vivo; inducible gene expression; insight; military service; motor neuron degeneration; mouse model; neuron loss; novel; novel therapeutic intervention; overexpression; protective efficacy; small molecule; sporadic amyotrophic lateral sclerosis; therapeutic target

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron degenerative disease that leads to paralysis and eventual death. ALS is a particular concern for veterans, as military service is associated with increased risk of ALS. The root cause of ALS is the death of motor neurons; however, the modalities of motor neuron death in ALS remain unclear. Ferroptosis is an oxidative, iron-dependent cell death mechanism. Results from our prior research have shown that motor neurons are vulnerable to ferroptosis. Importantly, we showed recently that increased defense against ferroptosis resulted in significantly increased lifespan and ameliorated motor neuron degeneration in SOD1G93A mice, a widely used ALS mouse model, indicating that ferroptosis is a targetable vulnerability of motor neurons. However, at present, key questions about the roles of ferroptosis in motor neuron death of ALS remain unanswered. For example, it is unclear whether inhibition of ferroptosis at symptomatic stage can retard progression of motor neuron disease, and the contributions of ferroptotic stress of different cell types on pathogenesis of motor neuron disease remain unknown. To answer those questions, we have generated a novel mouse model with inducible expression of Gpx4, the master defender of ferroptosis, which allows us to inhibit ferroptosis genetically in both temporal and cell-type specific manners. In our preliminary study, we have also identified a small molecule compound with the ability to retard ferroptosis of motor neurons in vivo. To determine if ferroptosis-inhibiting compounds can retard motor neuron disease, we will test the efficacy of this compound in SOD1G93A mice. The overall hypothesis tested in this project is: inhibition of ferroptosis after disease onset will be effective in retarding progression of motor neuron disease and ferroptosis inhibition retards motor neuron disease in a cell-type specific manner. The results from this project will provide novel insights into the mechanisms of motor neuron degeneration of ALS, and importantly, could lead to new therapeutic strategies for ALS.

肌萎缩侧索硬化症（ALS）是一种破坏性的运动神经元退行性疾病， 瘫痪并最终死亡ALS是退伍军人特别关注的问题，因为兵役与 增加ALS的风险。ALS的根本原因是运动神经元的死亡;然而，运动神经元的形态 ALS中的神经元死亡仍不清楚。铁凋亡是一种氧化性、铁依赖性细胞死亡机制。结果 我们先前的研究表明运动神经元容易发生铁凋亡。重要的是，我们展示了 最近，增加对铁凋亡的防御导致寿命显着增加， SOD 1G 93 A小鼠（一种广泛使用的ALS小鼠模型）的运动神经元变性，表明铁凋亡是 运动神经元的一个有针对性的弱点。然而，目前，关于铁凋亡作用的关键问题， 运动神经元死亡的ALS仍然没有答案。例如，目前还不清楚是否抑制铁凋亡， 症状阶段可以延缓运动神经元疾病的进展， 不同细胞类型对运动神经元疾病发病机制的影响尚不清楚。为了回答这些问题，我们 已经产生了一种新的小鼠模型，其具有Gpx 4的诱导表达，Gpx 4是铁凋亡的主要防御者， 这使得我们能够以时间和细胞类型特异性方式遗传性地抑制铁凋亡。在我们 在初步研究中，我们还鉴定了一种小分子化合物，其具有延缓铁凋亡的能力。 体内运动神经元为了确定抑制铁中毒的化合物是否能延缓运动神经元疾病，我们 将测试该化合物在SOD 1G 93 A小鼠中的功效。本项目检验的总体假设为： 在疾病发作后抑制铁下垂将有效延缓运动神经元疾病的进展， 铁凋亡抑制以细胞类型特异性方式延缓运动神经元疾病。这个项目的成果 将为ALS运动神经元变性的机制提供新的见解，重要的是， 导致ALS的新治疗策略。