Post-transcriptional regulations of proteomes in stress and senescence

应激和衰老中蛋白质组的转录后调控

• 批准号: 10706962
• 负责人: Maggie Lam
• 金额: $ 49.56万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706962
• 关键词: Age; Aging; Alternative Splicing; Area; Atlases; Biochemical; Biological; Cell Culture Techniques; Cell physiology; Cells; Cellular Stress; Chemicals; Code; Data; Data Set; Disease; Doxorubicin; Exons; Gene Expression; Genes; Goals; Human; Hydrogen Peroxide; In Vitro; Individual; Intervention; Knowledge; Lesion; Link; Locales; Mass Spectrum Analysis; Messenger RNA; Methods; Modeling; Multiomic Data; Organism; Output; Oxidative Stress; Paraquat; Phase; Physiological; Physiology; Play; Post-Transcriptional Regulation; Protein Biosynthesis; Protein Dynamics; Protein Isoforms; Proteins; Proteome; Proteomics; RNA; RNA Splicing; RNA-Binding Proteins; RNA-Protein Interaction; Regulation; Ribosomes; Role; Shapes; Spatial Distribution; Stable Isotope Labeling; Stimulus; Stress; Structure; System; Techniques; Technology; Time; Tissues; Transcript; Translating; Translations; Work; aged; biological adaptation to stress; cellular targeting; crosslink; design; differential expression; experimental study; in vivo; innovation; insight; method development; multiple omics; novel; posttranscriptional; protein crosslink; protein function; proteostasis; resilience; response; senescence; spatiotemporal; stoichiometry; stress granule; stress resilience; stressor; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Post-transcriptional mechanisms play a fundamental role in regulating gene expression at the protein level, and are frequently implicated in stress response, aging, and diseases. The goal of this project is to develop and apply multi-omics methods to examine the post-transcriptional mechanisms that regulate protein composition of multiple tissues and their ability to respond to proteostatic stressors. In recent work, our team has developed mass spectrometry and multi-omics methods that are designed to elucidate the protein isoform composition and spatiotemporal dynamics. Building on these progresses, we will focus here on the roles of three post-transcriptional mechanisms known to influence protein translation in stress response. Specifically, Aim 1 will integrate proteomics and transcriptomics data to identify the role of alternative splicing in modulating principal isoform abundance, creating alternative proteoforms, and influencing protein localization in mammalian tissues. Aim 2 will determine the differential expression, localization, and targets of RNA-binding proteins in proteostatic stress responses including paraquat in vivo as well as doxorubicin and hydrogen peroxide in vitro. Finally, Aim 3 will examine the configuration and interactome of the translation apparatus including the core ribosome and an increasing number of known ribosome-associated proteins, which have emerged as important factors that can fine-tune the translational efficiency of individual transcripts and the associated protein synthesis rates. The proposed experiments will interrogate the relationships between post-transcriptional regulation and stress response, and at the same time generate novel data sets including isoform-resolved, spatiotemporal atlases of the normal, stressed, and aged/senescent proteomes. We anticipate the results will lead to novel insights into basic cellular processes of stress response and resilience that will be relevant to studies of multiple systems.

项目摘要 转录后机制在蛋白质水平调节基因表达方面发挥着重要作用， 并且经常与应激反应、衰老和疾病有关。该项目的目标是开发 并应用多组学方法研究调控蛋白质的转录后机制 多个组织的组成和它们对蛋白质抑制应激源的响应能力。在最近的工作中，我们的团队 已经开发了质谱和多组学方法，旨在阐明蛋白质亚型 组成和时空动力学。在这些进展的基础上，我们将在这里重点讨论以下方面的作用： 三种已知影响应激反应中蛋白质翻译的转录后机制。 具体来说，Aim 1将整合蛋白质组学和转录组学数据，以确定替代基因的作用。 剪接调节主要同种型丰度，产生替代蛋白质型，并影响蛋白质 在哺乳动物组织中的定位。目标2将确定差异表达、定位和靶点 RNA结合蛋白在蛋白抑制应激反应中的作用，包括体内百草枯和阿霉素 和过氧化氢。最后，目标3将检查翻译的结构和相互作用 包括核心核糖体和越来越多的已知核糖体相关蛋白的装置， 这已经成为可以微调单个转录本翻译效率的重要因素 以及相关的蛋白质合成速率。 拟议的实验将询问转录后调控之间的关系， 和应激反应，并在同一时间产生新的数据集，包括异构体解决， 正常、应激和老化/衰老蛋白质组的时空图谱。我们预计结果将 导致对压力反应和恢复力的基本细胞过程的新见解， 多系统的研究。