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.

项目摘要/摘要 压力期间基因调节的保守机制是mRNA和 蛋白质进入无膜室被称为信使核糖核蛋白（MRNP）颗粒。 最近的研究暗示了这些颗粒的异常形成 神经退行性疾病。有人提出，对这些mRNA和蛋白质的错误定位对这些 病理夹杂物可以通过改变基因表达控制来引起有毒功能。我们的 研究计划旨在使用酵母中葡萄糖饥饿期间MRNP颗粒的形成 阐明有关这些膜的形成和功能的基本机械原理 隔间以及运用酵母的知识和技术专业知识来了解如何 与神经退行性疾病相关的RNA结合蛋白的相位分离会影响 哺乳动物细胞中的基因表达。这项研究以我们的发现为基础，在压力期间 转录和翻译可以耦合，因为启动子元素可以确定 mRNA至mRNP颗粒，从而影响其随后的翻译性。我们的策略将采取 两部分的方法。第一个方向将重点阐明启动子的机制 细胞核中的元素可以将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功能 酵母和哺乳动物细胞。这项研究将深入了解指定mRNA的基本问题 定位到无膜室，以及这如何影响细胞的基因表达， 这对于理解有毒MRNP骨料可能对细胞可能对细胞产生的影响很重要 神经变性。