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.

肌萎缩性侧面硬化症（ALS）是一种毁灭性运动神经元退化性疾病，导致 瘫痪和最终死亡。 ALS是退伍军人的特别关注，因为兵役与 ALS的风险增加。 ALS的根本原因是运动神经元的死亡。但是，电机的方式 ALS中的神经元死亡尚不清楚。铁凋亡是一种氧化，铁依赖性细胞死亡机制。结果 从我们先前的研究中，运动神经元很容易受到铁毒性。重要的是，我们表明 最近，对铁铁作用的防御增加导致寿命显着增加并改善 SOD1G93A小鼠中的运动神经元变性，一种广泛使用的ALS小鼠模型，表明铁铁病是 运动神经元的目标脆弱性。但是，目前，有关铁铁作用的关键问题 ALS的运动神经元死亡仍未得到答复。例如，目前尚不清楚抑制在 有症状的阶段会阻碍运动神经元疾病的进展，以及 运动神经元疾病发病机理的不同细胞类型尚不清楚。要回答这些问题，我们 已经产生了一种新型的小鼠模型，具有诱导表达的GPX4，是铁肉食的主要防御者， 这使我们能够在特定的时间和细胞类型的特定方式中抑制遗传性的铁毒性。在我们的 初步研究，我们还确定了一种小分子化合物，能够延缓 运动神经元在体内。为了确定抑制抑制氟凋亡的化合物是否会阻碍运动神经元疾病，我们 将测试该化合物在SOD1G93A小鼠中的功效。该项目中检验的总体假设是： 疾病发作后抑制铁凋亡将有效地延迟运动神经元疾病的进展和 铁凋亡抑制以细胞类型的特异性方式抑制运动神经元疾病。这个项目的结果 将提供有关ALS运动神经元变性机制的新见解，重要的是 导致ALS的新治疗策略。