Determination of cell death pathways activated in ALS

ALS 中激活的细胞死亡途径的测定

• 批准号: 9277077
• 负责人: Wan S. Yang
• 金额: $ 16.4万
• 依托单位: ST. JOHN'S UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277077
• 关键词: Adult; Affect; Amyotrophic Lateral Sclerosis; Apoptosis; Apoptotic; Autopsy; Award; BCL2 gene; Biomedical Research; C9ORF72; Caspase Inhibitor; Cell Death; Cell Line; Cell model; Cells; Cessation of life; Combined Modality Therapy; DNA cassette; Data; Development; Disease; Disease Progression; Dominant-Negative Mutation; Environment; Familial Amyotrophic Lateral Sclerosis; Future; Genes; Glutamates; Goals; Immunohistochemistry; In Vitro; Individual; Inhibition of Apoptosis; Investigation; Knock-out; Lead; Learning; Light; Link; Lipid Peroxidation; Lipid Peroxides; Modality; Modeling; Molecular; Monitor; Motor; Motor Neuron Disease; Motor Neurons; Mus; Muscle Spasticity; Muscle Weakness; Muscular Atrophy; Mutation; Neurodegenerative Disorders; Neurons; PTGS2 gene; Pathway interactions; Patients; Phosphorylation; RIPK1 gene; RIPK3 gene; Reagent; Reporting; Research; Respiratory Failure; Role; Sampling; Spinal Cord; Students; Symptoms; Testing; Tissue Sample; Tissues; Transgenic Mice; Treatment Efficacy; Universities; Up-Regulation; Virus; base; career; cell determination; disability; genetic analysis; glutathione peroxidase; graduate student; human disease; in vivo; induced pluripotent stem cell; inhibitor/antagonist; interest; knock-down; motor neuron degeneration; motor neuron injury; mouse model; mutant; neuron loss; novel therapeutic intervention; protein TDP-43; small molecule; superoxide dismutase 1; therapy development; treatment strategy; undergraduate student

SUMMARY/ABSTRACT Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disorder that causes muscle weakness, disability, and eventually death. ALS is caused by selective cell death of vulnerable upper and lower motor neurons. Genetic analyses in familial ALS patients have identified several genes with mutations linked to ALS, such as C9ORF72, TDP-43, and SOD1. However, it remains unclear how these mutations lead to selective cell death of motor neurons in ALS patients, and which cell death pathways are responsible for the motor neuron cell death. Early studies suggested the involvement of apoptosis, but a more recent investigation found a role for necroptosis in one cell model. It is plausible that multiple cell death pathways are activated in the course of the disease. We recently reported that inhibition of glutathione peroxidase 4 (GPX4), and subsequent accumulation of lipid peroxides, triggers a unique form of regulated cell death termed ferroptosis. Intriguingly, data from multiple ALS models as well as our own results have suggested that ferroptosis may contribute to the motor neuron cell death in ALS. Based on the experimental results indicating the role of both apoptotic and non-apoptotic cell death pathways in ALS, I propose to test the hypothesis that multiple cell death pathways are activated in ALS motor neurons, focusing on the involvement of ferroptosis. Our long-term goal is to elucidate how cell death pathways are regulated (and deregulated) in human disease, and to contribute to the development of treatment strategies by modulating cell death pathways. We are particularly interested in understanding the ferroptotic cell death pathway. The objective of this proposal is to determine cell death pathways activated in degenerating motor neurons in amyotrophic lateral sclerosis (ALS) focused on the involvement of ferroptosis. Based on the preliminary data, the project will be pursued in two specific aims. In Aim 1, we will identify the specific cell death pathways involved in ALS using motor neuron lines (iPS-MNs) in vitro and using a transgenic mouse model of ALS in vivo. In Aim 2, we will determine the efficacy of ferroptosis inhibitor in ALS iPS-MN cell lines and in SOD1-G93A transgenic mice either as a single-agent or as a combination therapy with suppressors of other cell death modalities. This research will shed light on the molecular mechanism of motor neuron degeneration in ALS, as well as the role of ferroptosis in the disease. It may also lead to the development of new therapeutic strategies. In addition, this SCORE-2 award will enhance the research environment at St. John's University and provide numerous opportunities for motivated students from diverse origin to learn the fundamentals of biomedical research.

总结/摘要 肌萎缩性侧索硬化症（ALS）是运动神经元疾病的最常见形式，其导致肌肉萎缩。 虚弱残疾最终死亡肌萎缩侧索硬化症是由脆弱的上、下肌层的选择性细胞死亡引起的。 运动神经元家族性ALS患者的遗传分析已经确定了几个与ALS相关的突变基因。 ALS，如C9ORF72、TDP-43和SOD1。然而，目前尚不清楚这些突变如何导致 ALS患者中运动神经元的选择性细胞死亡，以及哪些细胞死亡途径负责 运动神经元细胞死亡早期的研究表明细胞凋亡的参与，但最近的调查， 在一个细胞模型中发现了坏死性凋亡的作用。这是合理的，多个细胞死亡途径被激活， 疾病的进程。我们最近报道，谷胱甘肽过氧化物酶4（GPX 4），和 脂质过氧化物随后的积累触发了一种独特的调节性细胞死亡形式，称为铁凋亡。 有趣的是，来自多个ALS模型的数据以及我们自己的结果表明， 导致ALS中运动神经元细胞死亡。根据实验结果表明，两者的作用 凋亡和非凋亡细胞死亡途径在ALS，我建议测试的假设，多细胞 死亡途径在ALS运动神经元中被激活，集中于铁凋亡的参与。我们的长期 目的是阐明细胞死亡途径在人类疾病中是如何调节（和解除调节）的， 有助于通过调节细胞死亡途径来开发治疗策略。我们特别 有兴趣了解铁凋亡细胞死亡途径。本提案的目的是确定 肌萎缩侧索硬化症（ALS）中退化运动神经元中激活的细胞死亡途径， 铁性下垂症根据初步数据，该项目将在两个具体目标下开展。 在目标1中，我们将使用运动神经元系（iPS-MN）来确定ALS中涉及的特定细胞死亡途径。 在体外和在体内使用ALS的转基因小鼠模型。在目标2中，我们将确定 在ALS iPS-MN细胞系和SOD1-G93A转基因小鼠中， 与其他细胞死亡形式的抑制剂的组合疗法。这项研究将阐明 肌萎缩侧索硬化症运动神经元变性的分子机制，以及铁凋亡在疾病中的作用。它 也可能导致新的治疗策略的发展。此外，该SCORE-2奖项将提高 圣约翰大学的研究环境，并为积极进取的学生提供了许多机会 从不同的起源，学习生物医学研究的基础知识。