Function of the oxidoreductase PYROXD1 in axon regeneration

氧化还原酶PYROXD1在轴突再生中的功能

• 批准号: 10730536
• 负责人: Carrie Ann Davison
• 金额: $ 3.26万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10730536
• 关键词: Address; Aging; Alleles; Axon; Basic Science; Biosensor; CRISPR/Cas technology; Caenorhabditis elegans; Cell Respiration; Chemistry; Clinical; Collaborations; Complex; Copper; Critical Thinking; Cytoplasm; Data; Defect; Dependence; Disease Progression; Environment; Enzyme Interaction; Enzymes; Fellowship; Genes; Genus Hippocampus; Goals; Health; Human; Human Cell Line; Injury; Interneurons; Lead; Ligation; Limb structure; Mediating; Messenger RNA; Mitochondria; Molecular; Morphology; Motor Neurons; Mutation; Myopathy; Natural regeneration; Nervous System; Neuronal Injury; Neurons; Neurosciences; Oxidation-Reduction; Oxidative Regulation; Oxidative Stress; Oxidoreductase; Oxygen; Oxygen Consumption; Pathway interactions; Phenotype; Process; Proteins; RNA; RNA Ligase (ATP); RNA Processing; RNA Splicing; Regulation; Role; Stress; Technical Expertise; Testing; Training; Untranslated RNA; Work; academic preparation; axon injury; axon regeneration; career; clinically significant; early onset; endoplasmic reticulum stress; extracellular; functional restoration; gamma-Aminobutyric Acid; genetic analysis; in vivo; inhibitor; insight; loss of function; metalloenzyme; mitochondrial dysfunction; mutant; nerve damage; nervous system disorder; new therapeutic target; novel; pyridine nucleotide; regeneration model; regenerative; response; response to injury; tool; trafficking

Project Summary/Abstract Through axon regeneration, neurons restore function after injury. This conserved, complex process requires numerous cellular pathways including support of mitochondrial function and RNA processing. Mitochondria function is implicated in numerous neurological disorders, and dysfunction of mitochondria contributes to oxidative stress, a hallmark of aging. However, the role of the oxidative environment in axon regeneration has not been well characterized. Oxidoreductases are a diverse class of enzymes that regulate the oxidative environment of neurons. The oxidoreductase PYROXD1 is important for human health, and loss of PYROXD1 disrupts mitochondrial function and RNA-ligation by RtcB during the unfolded protein response. We found that PYROXD1 is necessary for axon regeneration; however, the mechanism by which PYROXD1 promotes regeneration is unknown. This proposal will elucidate the mechanism of PYROXD1 in axon regeneration in two independent aims. In Aim 1, the role of PYROXD1 in mitochondria function and localization in axons during injury will be determined. Mitochondria are critical for axon regeneration, and PYROXD1 is required for normal mitochondria function. Aim 1 will establish the relationship between PYROXD1 and mitochondria during axon regeneration, and will examine a suite of clinically-significant PYROXD1 mutations in this process. In Aim 2, the role of PYROXD1-protection of the RNA-ligase RtcB will be clarified. RtcB inhibits axon regeneration via a novel mechanism of non-canonical cytoplasmic splicing during the unfolded protein response. RtcB is dependent on copper, and this dependence makes it sensitive to inactivation in oxidative environments. Aim 2 will determine the sensitivity of RtcB to redox environment in vivo and define the relationship among PYROXD1, RtcB, and the unfolded protein response gene xbp-1 in regeneration. Upon completion of this fellowship, the trainee will have received extensive training in a supportive and collaborate environment. The project will further the trainee’s technical skills, critical thinking abilities, and independence in preparation for an academic career in molecular neuroscience. The results of this project will shed light on the importance of oxidative environment, mitochondria function, and RNA processing for successful axon regeneration.

项目概要/摘要 通过轴突再生，神经元在损伤后恢复功能，这个保守而复杂的过程需要。 许多细胞途径，包括支持线粒体功能和 RNA 加工。 功能与许多神经系统疾病有关，线粒体功能障碍导致 氧化应激是衰老的一个标志然而，氧化环境在轴突再生中的作用已经存在。 氧化还原酶是调节氧化的多种酶。 氧化还原酶 PYROXD1 对人类健康很重要，PYROXD1 的缺失也很重要。 我们发现，在未折叠的蛋白质反应过程中，RtcB 会破坏线粒体功能和 RNA 连接。 PYROXD1 对于轴突再生是必需的；然而，PYROXD1 促进的机制尚不清楚。 该提案将阐明 PYROXD1 在两种轴突再生中的机制。 在目标 1 中，PYROXD1 在损伤期间线粒体功能和轴突定位中的作用。 线粒体对于轴突再生至关重要，而 PYROXD1 是正常所必需的。 目标 1 将建立轴突过程中 PYROXD1 与线粒体之间的关系。 再生，并将检查该过程中一系列具有临床意义的 PYROXD1 突变。 PYROXD1 保护 RNA 连接酶 RtcB 的作用将得到阐明，RtcB 通过一种新的方法抑制轴突再生。 未折叠蛋白反应期间非规范细胞质剪接的机制取决于 RtcB。 铜，这种依赖性使其对氧化环境中的失活敏感，目标 2 将确定。 RtcB 对体内氧化还原环境的敏感性，并定义 PYROXD1、RtcB 和 完成本研究金后，学员将获得再生中未折叠的蛋白质反应基因 xbp-1。 在支持性和协作性的环境中接受广泛的培训 该项目将进一步促进学员的发展。 为分子学术生涯做准备的技术技能、批判性思维能力和独立性 该项目的结果将揭示氧化环境、线粒体的重要性。 功能和 RNA 加工以实现轴突的成功再生。