Regulation of protein synthesis by metabolic signals and the circadian clock

通过代谢信号和生物钟调节蛋白质合成

基本信息

批准号：
10797235
负责人：
Albrecht G. von ARNIM
金额：
$ 2.86万
依托单位：
UNIVERSITY OF TENNESSEE KNOXVILLE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-06-30
项目状态：
已结题

项目摘要

Project Summary Protein synthesis is a core function of all cells and is the target of multiple signaling pathways that coordinate the translation of mRNAs into proteins in response to exogenous and internal signals. Work from this and other laboratories has highlighted that cyclical signals from the light environment, temperature, metabolic biomarkers, and the circadian clock are integrated to coordinate mRNA ribosome loading on a genome-wide scale. Central in this network is the signaling axis known as the TOR-S6 kinase pathway. It regulates the phosphorylation of several components of the cytosolic translation apparatus including one prominent target on the ribosome, the eS6 protein located at the foot of the small ribosomal subunit. The model system underlying the current project, Arabidopsis thaliana, is not only representative of higher eukaryotes because of the conservation of its TOR-S6K-eS6 signaling channel, but is also an ideal system to study the integration of various cyclical signals in a chronobiological context. The first aim of the project builds on innovative and established molecular, biochemical, and cellular assays to tackle a long-standing question, the biochemical and cellular role of eS6-phosphorylation. Plants in which phosphorylation of eS6 is abolished or otherwise disrupted display at most minor defects in their growth, development, and transcriptome. Therefore, detailed assays of translational fidelity, ribosome biogenesis, translation, and autophagy will be refined and applied to identify the biochemical and cellular scope of eS6 phosphorylation. The second aim is a collaboration with a group of versatile computational biologists under co-investigator Tian Hong. As the cell processes multiple independent circadian signals, it can be predicted theoretically that the precise mode of their integration will lead to new circuit properties including complex waveforms or even ultradian periods. The project will use bioinformatic data mining, mathematical modeling, and wet-lab experimentation to distinguish between competing hypotheses to explain how multiple cyclical signals are integrated with each other.

项目概要蛋白质合成是所有细胞的核心功能，是协调多种信号通路的目标响应外源和内部信号将 mRNA 翻译成蛋白质。从这个和其他工作实验室强调，来自光环境、温度、代谢的周期性信号生物标志物和生物钟被整合以协调全基因组上的 mRNA 核糖体加载规模。该网络的中心是信号轴，称为 TOR-S6 激酶途径。它调节胞浆翻译装置的几个组件的磷酸化，包括一个突出的靶标核糖体，即位于核糖体小亚基底部的 eS6 蛋白。底层模型系统当前的项目拟南芥不仅是高等真核生物的代表，因为 TOR-S6K-eS6 信号通道的保护，但也是研究整合的理想系统时间生物学背景下的各种周期性信号。该项目的首要目标建立在创新和建立了分子、生化和细胞测定法来解决一个长期存在的问题，即生化和 eS6-磷酸化的细胞作用。 eS6 磷酸化被废除或以其他方式的植物被破坏的细胞在生长、发育和转录组方面至多表现出微小的缺陷。因此，详细翻译保真度、核糖体生物发生、翻译和自噬的测定将得到改进并应用于确定 eS6 磷酸化的生化和细胞范围。第二个目标是与联合研究员田宏领导下的一群多才多艺的计算生物学家。当细胞处理多种独立的昼夜节律信号，理论上可以预测它们整合的精确模式将导致新的电路特性，包括复杂的波形甚至超电周期。该项目将使用生物信息数据挖掘、数学建模和湿实验室实验来区分相互竞争的假设来解释多个周期性信号如何相互整合。