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

基本信息

批准号：
10342191
负责人：
Maggie Lam
金额：
$ 47.38万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/10342191
关键词：
Age Aging Alternative Splicing Area Atlases Biochemical Biological Cell Culture Techniques Cell physiology Cells Cellular Stress Response Chemicals Code Data Data Set Disease Doxorubicin Exons Gene Expression Genes Genetic Transcription Goals Human Hydrogen Peroxide In Vitro Individual Intervention Knowledge Lesion Link Locales Mass Spectrum Analysis Messenger RNA Methods Modeling 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 protein crosslink protein function proteostasis resilience response senescence spatiotemporal stoichiometry stress granule stress resilience stressor transcriptome sequencing transcriptomics

项目摘要

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调节蛋白质水平的基因表达方面起着基本作用，并经常与压力反应，衰老和疾病有关。该项目的目的是开发并采用多词方法来检查调节蛋白质的转录后机制多个组织的组成及其对蛋白质压力源反应的能力。在最近的工作中，我们的团队已经开发了旨在阐明蛋白质同工型的质谱和多媒体方法组成和时空动力学。在这些进展的基础上，我们将重点关注已知在应力反应中影响蛋白质翻译的三种后转录机制。具体而言，AIM 1将整合蛋白质组学和转录组学数据以识别替代方案的作用调节主同工型丰度，创建替代蛋白质和影响蛋白质的剪接在哺乳动物组织中定位。 AIM 2将确定差分表达，定位和目标蛋白质应激反应中的RNA结合蛋白的蛋白质，包括体内和阿霉素和过氧化氢在体外。最后，AIM 3将检查翻译的配置和互动组包括核心核糖体和越来越多的已知核糖体相关蛋白的设备，已经成为可以微调单个成绩单的翻译效率的重要因素以及相关的蛋白质合成速率。提出的实验将询问转录后调节之间的关系和压力响应，同时生成新的数据集，包括同工型解决，正常，压力和年龄/衰老蛋白质组的时空地图集。我们预计结果将会导致对压力反应和弹性的基本细胞过程的新见解，这将与多个系统的研究。