A new proteostasis checkpoint in Drosophila intestinal stem cells: implications for age-related tissue dysfunction

果蝇肠干细胞中的一个新的蛋白质稳态检查点:对年龄相关组织功能障碍的影响

基本信息

项目摘要

 DESCRIPTION (provided by applicant): Loss of proteostasis is a hallmark of aging. It has been proposed that this loss is due to a decline in many biological processes used by cells to regulate and maintain their proteins, from synthesis to degradation. Loss of proteostasis results in the accumulation of damaged proteins and aggregates, leading to impaired cellular function and cell death, as well as a range of age-related diseases, like Alzheimer's and Parkinson's disease. Cells that are particular sensitive to loss of proteostasis are the stem cells (SCs) found in regenerative tissues, such as the intestine. These somatic SCs are needed to regenerate tissues after normal cell attrition or in response to stress. Somatic SCs have been proposed to have unique mechanisms for maintaining their proteostatic capacity. However, these mechanisms are not completely understood. This proposal aims at understanding how somatic SCs maintain their proteostasis, why this is lost during the aging process, and at exploring ways of improving proteostasis in old tissues. To answer these questions, the applicant proposes studies using the fruit fly Drosophila melanogaster as a model organism. Through work by the mentor and others, the fly posterior midgut has emerged as a powerful genetically amenable system to study intestinal SC (ISC) function in the context of tissue regeneration and aging. In preliminary studies, the applicant has extended this work to develop an experimental paradigm to establish the effectiveness of protein aggregate clearance in ISCs under different environmental and genetic conditions in vivo. This work has led to the observation that ISCs react to protein aggregates by undergoing temporary cell cycle arrest while clearing aggregates, and that this arrest, as well as the ability to clear aggregates, declines with age. Based on these observations and on the current literature, the applicant hypothesizes that ISCs activate a 'proteostasis checkpoint' regulated by the transcription factor Nrf2/CncC whenever proteostasis is compromised. Nrf2/CncC is a master regulator of the antioxidant response that regulates ISC proliferation and controls the expression of genes encoding one of the degradation machineries, the proteasome. To test this hypothesis, the applicant proposes genetic studies in ISCs to: (i) assess the role of Nrf2/CncC in the proteostasis checkpoint and in aggregate clearance, (ii) explore the mechanism of aggregate clearance, and (iii) test if promoting proteostasis in old ISCs is sufficient to improve tissue homeostasis and survival. The proposed studies will characterize specific mechanisms by which somatic stem cells maintain protein homeostasis throughout life, and will gain insight into whether and how these mechanisms influence tissue homeostasis and survival. Based on the evolutionary conservation of many of the regulatory mechanisms studied in this research proposal, it can be anticipated that the findings obtained by this work will have important implications for human disease and aging.
 描述(由申请方提供):蛋白质稳态丧失是衰老的标志。有人提出,这种损失是由于细胞用于调节和维持其蛋白质的许多生物过程(从合成到降解)的下降。蛋白质稳态的丧失导致受损蛋白质和聚集体的积累,导致细胞功能受损和细胞死亡,以及一系列与年龄相关的疾病,如阿尔茨海默病和帕金森病。对蛋白质稳态丧失特别敏感的细胞是发现的干细胞(SC) 在再生组织中,比如肠道。这些体细胞SC是正常细胞磨损或应激后再生组织所必需的。体细胞SC被认为具有独特的机制来维持其蛋白抑制能力。然而,这些机制尚未完全理解。该提案旨在了解体细胞SC如何维持其蛋白质稳态,为什么这在衰老过程中丢失,并探索改善旧组织蛋白质稳态的方法。为了回答这些问题,申请人提出了使用果蝇Drosophila melanogaster作为模式生物的研究。通过导师和其他人的工作,苍蝇后中肠已经成为一个强大的遗传适应系统,以研究组织再生和衰老背景下的肠道SC(ISC)功能。在初步研究中,申请人已经将这项工作扩展到开发实验范例,以确定在体内不同环境和遗传条件下ISC中蛋白质聚集体清除的有效性。这项工作已经导致观察到,ISCs通过在清除聚集体的同时经历暂时的细胞周期停滞来对蛋白质聚集体做出反应,并且这种停滞以及清除聚集体的能力随着年龄的增长而下降。基于这些 根据观察结果和当前文献,申请人假设每当蛋白质稳态受损时,ISC激活由转录因子Nrf 2/CncC调节的“蛋白质稳态检查点”。Nrf 2/CncC是抗氧化反应的主要调节因子,其调节ISC增殖并控制编码降解机制之一蛋白酶体的基因的表达。为了检验这一假设,申请人提出在ISC中进行遗传研究以:(i)评估Nrf 2/CncC在蛋白质稳态检查点和聚集体清除中的作用,(ii)探索聚集体清除的机制,以及(iii)检验促进旧ISC中的蛋白质稳态是否足以改善组织稳态和存活。拟议的研究将表征体干细胞在整个生命过程中维持蛋白质稳态的特定机制,并将深入了解这些机制是否以及如何影响组织稳态和存活。基于本研究提案中研究的许多调节机制的进化保守性,可以预期,这项工作所获得的发现将对人类疾病和衰老产生重要影响。

项目成果

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