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.

项目总结/摘要 损伤后神经元通过轴突再生恢复功能。这个保守的复杂过程需要 许多细胞途径，包括支持线粒体功能和RNA加工。线粒体 线粒体功能障碍与许多神经系统疾病有关，线粒体功能障碍有助于 氧化应激是衰老的标志然而，氧化环境在轴突再生中的作用， 没有被很好地描述。氧化还原酶是调节氧化还原酶活性的多种酶。 神经元的环境氧化还原酶PYROXD 1对人类健康很重要，PYROXD 1的损失 在未折叠蛋白质反应期间破坏线粒体功能和RtcB的RNA连接。我们发现 PYROXD 1是轴突再生所必需的;然而，PYROXD 1促进轴突再生的机制是不确定的。 再生未知。本研究将阐明PYROXD 1在两种神经元轴突再生中的作用机制。 独立的目标。在目的1中，PYROXD 1在损伤过程中线粒体功能和轴突定位中的作用 将被确定。线粒体对轴突再生至关重要，而PYROXD 1是正常轴突再生所必需的。 线粒体功能目的1建立PYROXD 1在轴突生长过程中与线粒体的关系 再生，并将检查在这个过程中的一套具有临床意义的PYROXD 1突变。在目标2中， 将阐明RNA连接酶RtcB的PYROXD 1保护作用。RtcB通过一种新的途径抑制轴突再生 未折叠蛋白质反应期间的非规范胞质剪接机制。RtcB依赖于 铜，这种依赖性使其在氧化环境中对失活敏感。目标2将决定 RtcB对体内氧化还原环境的敏感性，并确定PYROXD 1，RtcB和 未折叠蛋白反应基因xbp-1在再生中的作用。在完成这项研究后，受训人员将拥有 在支持和合作的环境中接受了广泛的培训。该项目将进一步促进受训者的 技术技能，批判性思维能力和独立性，为分子领域的学术生涯做准备 神经科学该项目的结果将阐明氧化环境，线粒体 功能和RNA加工成功的轴突再生。