Identification of longevity targets in C. elegans protein translation mutants

描述（由申请人提供）：这项研究提出的申请解决了一个非常有趣的问题，在衰老和mRNA翻译领域：为什么许多生物体，包括线虫C。在mRNA翻译机制的关键组成部分有缺陷的线虫是长寿和抗应激的？有趣的是，在应对环境胁迫时，所有真核细胞都关闭了它们的生物合成活性，并启动了整合的胁迫反应。在恢复过程中，某些蛋白质在一般翻译抑制的背景下产生。本申请的主要目的是揭示能够使应激诱导的mRNA在应激反应期间从翻译抑制中逃逸的生化机制以及参与长寿表型的主动翻译的mRNA。该项目将研究属于S6激酶（S6 K）和/或真核生物翻译起始因子（eIFs）组的关键翻译调控因子可以特异性介导这种逃逸的假设。重点将放在rsks-1/S6 K以及ife-2/eIF 4 E上，ife-2/eIF 4 E是蠕虫中的五种亚型之一，是mRNA 5 '帽结合蛋白。S6 K和eIF 4 E可能是调节介导应激特异性和寿命翻译的途径的核心。要解决的主要问题是：什么是S6 K和eIF 4 E下游的翻译目标，需要合成，以允许生存的压力和老化？这个问题将通过一系列尖端的核糖组学和蛋白质组学方法来解决。elegans作为一个实验系统。这种模式生物对衰老研究非常有用，因为它发育迅速，寿命短，并且能够通过RNAi轻松敲除基因。 与公共卫生的关系：人口老龄化正在迅速发展，并在21世纪成为一个深刻的全球人口趋势。然而，这种进展在细胞和分子水平上都知之甚少。该提案旨在确定mRNA翻译是一种受到严格调控的细胞过程，在生长，繁殖以及响应营养可用性和能量水平的生存过程中影响生物体，如何调节生物体衰老和抗应激能力。由于在许多生物体中观察到与年龄相关的蛋白质合成率下降，这项研究可能与理解蛋白质合成在人类衰老中的作用直接相关。

DESCRIPTION (provided by applicant): The research proposed in this fellowship application addresses an extremely interesting question in the field of aging and mRNA translation: How come many organisms, including the nematode C. elegans defective in key components of the mRNA translational machinery are long-lived and stress resistant? Interestingly, in response to environmental stress, all eukaryotic cells shut down their biosynthetic activity and mount an integrated stress response. During recovery, certain proteins are produced against the backdrop of general translational repression. The main objective of the present application is to uncover the biochemical mechanisms that enable the escape of stress-induced mRNAs from translational repression during the stress response and the actively translated mRNAs involved in the longevity phenotype. The project will examine the hypothesis that key translational regulatory factors belonging to either S6 kinase (S6K) and/or the group of eukaryotic translation initiation factors (eIFs) can specifically mediate this escape. The focus will be on rsks-1/ S6K, as well as on ife-2/eIF4E, one of five isoforms in worms that is an mRNA 5'-cap binding protein. Both S6K and eIF4E may be at the heart of regulating a pathway that mediates stress-specific and longevity translation. The main question to be addressed is: What are S6K and eIF4E downstream translational targets that need to be synthesized in order to allow survival under stress and aging? This question will be addressed with a series of cutting-edge ribonomic and proteomic approaches using the nematode, C. elegans as an experimental system. The model organism is extremely useful for aging research because of its rapid development, short lifespan, and the ability to knock-out genes through RNAi with great ease. PUBLIC HEALTH RELEVANCE: Population aging is progressing rapidly and is having a profound global demographic trend in the twenty-first century. However, this progression is poorly understood at both the cellular and molecular level. This proposal aims to determine how mRNA translation, which is a tightly regulated cellular process that affects an organism during growth, reproduction, as well as survival in response to nutrient availability and energy levels, modulates organismal aging and stress resistance. As an age-related decline in protein synthesis rate is observed in many organisms, this research might have direct relevance for understanding the role of protein synthesis in human aging.