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: 10797686
• 负责人: Maggie Lam
• 金额: $ 25万
• 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/10797686
• 关键词: Acceleration; Administrative Supplement; Aging; Alternative Splicing; Atlases; Brain; Cell Culture Techniques; Cell physiology; Data; Data Set; Disease; Doxorubicin; Gene Expression; Goals; Heart; Human; Hydrogen Peroxide; In Vitro; Individual; Infrastructure; Longevity; Lung; Mass Spectrum Analysis; Methods; Modeling; Modernization; Muscle; Organism; Paraquat; Physiological; Play; Post-Transcriptional Regulation; Productivity; Protein Biosynthesis; Protein Isoforms; Proteins; Proteome; Proteomics; RNA-Binding Proteins; Research; Ribosomes; Role; Stimulus; Stress; System; Technology; Time; Tissues; Transcript; Translations; Work; aged; biological adaptation to stress; design; differential expression; experimental study; in vivo; insight; multiple omics; novel; parent project; posttranscriptional; resilience; response; senescence; sex; spatiotemporal; stress resilience; stressor; transcriptomics

Project Summary This administrative supplement application is being submitted to PA-20-272 in accordance with NOT-GM-22- 017. The scope of the parent project R01-GM144456 will not be changed. The requested supplement will replace critical hardware infrastructure to accelerate our research with modern capabilities and permit increased productivity. Parent 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 intrinsic and environmental 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 across tissues (heart, lung, muscle, brain), sexes, and lifespan. Aim 2 will determine the differential expression, localization, and targets of RNA-binding proteins in proteostatic stress responses to intrinsic or extrinsic stressors 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 根据NOT-GM-22，向PA-20-272提交本行政补充申请， 017.母项目R 01-GM 144456的范围将不会变更。所要求的补充将取代 关键的硬件基础设施，以加快我们的研究与现代化的能力，并允许增加 生产力母项目摘要：转录后机制在调节 在蛋白质水平的基因表达，并经常涉及应激反应，衰老和疾病。的 本项目的目标是开发和应用多组学方法来检测转录后 调节多种组织的蛋白质组成的机制及其对内源性和 环境蛋白质稳定性压力源。在最近的工作中，我们的团队开发了质谱和多- 设计用于阐明蛋白质异构体组成和时空动力学的组学方法。 在此基础上，我们将重点介绍三种已知的转录后机制的作用， 来影响应激反应中的蛋白质翻译。具体来说，目标1将整合蛋白质组学和 转录组学数据来鉴定可变剪接在调节主要同种型丰度中的作用， 产生替代蛋白质形式，并影响蛋白质在组织（心脏、肺、肌肉、脑）中的定位， 性别和寿命目的2将确定RNA结合的差异表达、定位和靶点 蛋白质在体内对包括百草枯在内的内在或外在应激源的蛋白质抑制应激反应中的作用， 阿霉素和过氧化氢体外。最后，目标3将检查 翻译装置包括核心核糖体和越来越多的已知核糖体， 相关的蛋白质，这已经成为重要的因素，可以微调的翻译效率， 单个转录本和相关蛋白质合成速率。拟议的实验将询问 转录后调节和应激反应之间的关系，同时产生新的 数据集，包括正常、应激和老化/衰老的异构体分辨时空图谱 蛋白质组我们预计这些结果将导致对应激反应的基本细胞过程的新见解 和复原力，这将与多系统的研究有关。