Investigation of copper homeostasis mRNAs regulated by the Nonsense-mediated mRNA decay pathway

由 Nonsense 介导的 mRNA 衰减途径调节的铜稳态 mRNA 的研究

• 批准号: 9232430
• 负责人: Bessie W Kebaara
• 金额: $ 41.29万
• 依托单位: BAYLOR UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-16 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232430
• 关键词: Accounting; Adverse effects; Affect; Cell physiology; Copper; Data; Degradation Pathway; Drosophila genus; Environment; Environmental Impact; Gene Expression; Gene Expression Regulation; Genes; Goals; Hereditary Disease; Homeostasis; Human; Human Genetics; Investigation; Knowledge; Lead; Mediating; Messenger RNA; Nonsense Codon; Nonsense Mutation; Organism; Pathway interactions; Physiological; Play; Production; Proteins; Regulation; Research; Role; Saccharomyces cerevisiae; System; Terminator Codon; Testing; Time; Untranslated Regions; Work; Yeasts; base; environmental change; functional group; insight; interest; mRNA Decay; mRNA Transcript Degradation; premature; prevent; response; therapy development; transcription factor USF; transcriptome

PROJECT SUMMARY The nonsense-mediated mRNA decay (NMD) pathway is a specialized pathway that contributes to the recognition and rapid degradation of mRNA with premature termination codons. This prevents the production of non-functional, potentially harmful truncated proteins. NMD affects the expression of a number of human genetic diseases by modulating the expression of genes carrying nonsense mutations. NMD also regulates the expression of specific genes by degrading natural mRNAs. Regulation of natural mRNAs by NMD has been identified in numerous organisms ranging from yeast to humans. However, the extent and reason for the targeting of most of these natural mRNAs is generally unknown and could be a way to support a proper cellular response to changing environmental conditions. The objective of this study is to investigate the role NMD plays in copper homeostasis. We hypothesize that mRNAs involved in copper homeostasis and are sensitive to NMD are regulated by the pathway through similar features. In addition, we postulate that the regulation of these mRNAs by NMD is responsive to environmental conditions. This hypothesis is formulated based on our preliminary observations showing that four mRNAs involved in copper homeostasis have identical NMD-targeting features. Additionally, regulation of one of the mRNAs by NMD is responsive to environment copper levels. This research will determine the extent to which functionally related mRNAs are regulated by NMD due to similar features. In addition, it will demonstrate the extent to which this regulation is responsive to environmental conditions. We plan to test our central hypothesis and accomplish the overall objective of this project by pursuing the following specific aims. In Aim 1 we will determine the features/factors that target mRNAs involved in copper homeostasis to NMD. In Aim 2 we will determine the environmental impact on the regulation of these mRNAs by NMD and the physiological consequences resulting from this regulation The contributions of this research is that it will demonstrate the extent to which natural mRNAs from the same functional group are regulated by NMD and the influence the environment has on this regulation. Successful completion of these studies would demonstrate for the first time the effect environmental conditions have on the regulation of functionally related mRNAs by NMD. This knowledge will allow the categorization of cellular processes regulated NMD, and lead to a more complete understanding of gene regulation in the genetically tractable organism S. cerevisiae. It is important to understand natural mRNA regulation by NMD given that these mRNAs are found in multiple organisms including humans and the strategies used by S. cerevisiae to regulate functionally related mRNAs could be utilized in other systems and under other conditions. Furthermore, The NMD pathway in humans is being targeted to treat genetic diseases caused by genes that contain nonsense codons.

项目摘要 无义介导的mRNA衰变（NMD）途径是一种专门的途径，有助于 识别和快速降解具有提前终止密码子的mRNA。这防止 产生无功能的、潜在有害的截短蛋白质。NMD影响数字的表达 通过调节携带无义突变的基因的表达来治疗人类遗传疾病。NMD还 通过降解天然mRNA来调节特定基因的表达。天然mRNA的调节 NMD已经在从酵母到人类的许多生物体中被鉴定。然而，程度和 靶向大多数这些天然mRNA的原因通常是未知的，并且可能是一种方法， 支持细胞对变化的环境条件做出适当的反应。本研究的目的是 研究NMD在铜稳态中的作用。我们假设参与铜的mRNA 体内平衡和对NMD敏感的细胞通过类似的特征由通路调节。此外，本发明还提供了一种方法， 我们假设NMD对这些mRNA的调节对环境条件有反应。这 基于我们的初步观察，我们提出了一个假设，表明四种mRNA参与了 铜稳态具有相同的NMD靶向特征。此外，通过调节一种mRNA， NMD对环境铜水平有响应。这项研究将确定在多大程度上， 功能相关的mRNA由于相似的特征而受到NMD的调节。此外，它还将展示 该法规对环境条件的响应程度。我们计划测试我们的中央 假设并通过追求以下具体目标实现本项目的总体目标。在 目的1我们将确定参与铜稳态的靶向mRNA的特征/因素。在 目的2：我们将确定环境对NMD调控这些mRNA的影响， 这项研究的贡献是，它将 证明来自相同功能组的天然mRNA受NMD调节的程度， 环境对这一规则的影响。成功完成这些研究将 首次证明了环境条件对功能调节的影响 通过NMD的相关mRNA。这种知识将允许对受NMD调节的细胞过程进行分类， 并导致对遗传上易处理的生物体S中的基因调控的更完整的理解。 啤酒。重要的是要了解NMD对自然mRNA的调节，因为这些mRNA是 在包括人类在内的多种生物体中发现，以及S.酿酒酵母调节 功能上相关的mRNA可用于其它系统和其它条件下。而且 人类的NMD途径被靶向治疗由含有以下基因的基因引起的遗传疾病： 无意义密码子