Causes and consequences of differential mRNA localization to mRNP granules

mRNA 定位到 mRNP 颗粒差异的原因和后果

• 批准号: 9750749
• 负责人: Brian Matthew Zid
• 金额: $ 38.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-25 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750749
• 关键词: Affect; Cell Nucleus; Cells; Coupled; Cytoplasm; Cytoplasmic Granules; Elements; Gene Expression; Gene Expression Regulation; Genetic Transcription; Glucose; Knowledge; Mammalian Cell; Membrane; Messenger RNA; Nerve Degeneration; Neurodegenerative Disorders; Pathologic; Pathology; Phase; Proteins; RNA; RNA-Binding Proteins; Research; Specific qualifier value; Starvation; Stress; Technical Expertise; Toxic effect; Translations; Yeasts; gain of function; insight; messenger ribonucleoprotein; programs; promoter; protein aggregate; protein expression

Project Summary/Abstract A conserved mechanism of gene regulation during stress is the phase separation of mRNA and proteins into membrane-less compartments termed messenger ribonucleoprotein (mRNP) granules. Recent research has implicated aberrant formation of these granules in the pathology of a variety of neurodegenerative diseases. It has been proposed that mislocalization of mRNAs and proteins to these pathological inclusions can cause a toxic gain-of-function through altered gene expression control. Our research program aims to use the formation of mRNP granules during glucose starvation in yeast to elucidate basic mechanistic principles about the formation and function of these membrane-less compartments as well as to apply the knowledge and technical expertise from yeast to understand how phase separation of RNA-binding proteins associated with neurodegenerative diseases impinge upon gene expression in mammalian cells. This research builds on our discovery that during stress, transcription and translation can be coupled, as promoter elements can determine the localization of mRNAs to mRNP granules, thereby impinging on their subsequent translatability. Our strategy will take a two-part approach. The first direction will focus on elucidating the mechanism by which promoter elements in the nucleus can direct the localization of mRNAs to mRNP granules in the cytoplasm. Second, we will explore the function that this differential localization has on the gene expression of yeast and mammalian cells. This research will give insight into basic questions of what specifies mRNA localization to membrane-less compartments and how this affects the gene expression of the cell, which is important for understanding the effects that toxic mRNP aggregates may have on cells during neurodegeneration.

项目总结/摘要 胁迫期间基因调控的保守机制是mRNA的相分离， 蛋白质进入称为信使核糖核蛋白（mRNP）颗粒的无膜区室。 最近的研究表明，这些颗粒的异常形成与多种肿瘤的病理学有关。 神经退行性疾病已经提出，mRNA和蛋白质与这些蛋白质的错误定位可能是导致这些蛋白质的错误定位的原因。 病理性内含物可通过改变基因表达控制而导致毒性功能获得。我们 研究计划旨在利用酵母中葡萄糖饥饿期间mRNP颗粒的形成， 阐明了这些无膜细胞的形成和功能的基本机理， 以及应用酵母的知识和技术专长，以了解如何 与神经退行性疾病相关的RNA结合蛋白质的相分离 在哺乳动物细胞中的基因表达。这项研究建立在我们的发现之上， 转录和翻译可以是偶联的，因为启动子元件可以决定转录和翻译的定位。 mRNA与mRNP颗粒结合，从而影响其随后的可翻译性。我们的策略是 一个两部分的方法。第一个方向将侧重于阐明启动子 细胞核中的元件可以指导mRNA定位于细胞质中的mRNP颗粒。 其次，我们将探讨这种差异定位对基因表达的作用， 酵母和哺乳动物细胞。这项研究将深入了解什么指定mRNA的基本问题 定位于无膜区室以及这如何影响细胞的基因表达， 这对于理解毒性mRNP聚集体在细胞增殖过程中对细胞的影响是重要的。 神经变性