Modeling DR and mRNA translation to understand adaptive mechanisms that promote health

对 DR 和 mRNA 翻译进行建模以了解促进健康的适应性机制

• 批准号: 10611984
• 负责人: ARIC N ROGERS
• 金额: $ 37.35万
• 依托单位: MOUNT DESERT ISLAND BIOLOGICAL LAB
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10611984
• 关键词: Address; Age; Aging; Alzheimer' s Disease; Binding; Binding Proteins; Biochemistry; Caenorhabditis elegans; Cell physiology; Cellular Stress; Complex; Cytoprotection; Data; Development; Feedback; Fertility; Food; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Germ Cells; Goals; HSF1; Health; Health Promotion; Heat shock proteins; Heat-Shock Proteins 90; Heat-Shock Response; Longevity; Malnutrition; Messenger RNA; Modeling; Molecular Chaperones; Mus; Muscle; Muscle function; Muscular Atrophy; Nature; Neurons; Nutrient; Nutrient availability; Orthologous Gene; Parkinson Disease; Pathway interactions; Physical activity; Physiological; Proteins; Quality Control; RNA Interference; RNA-Binding Proteins; Regulation; Reporting; Reproduction; Resistance; Risk; Role; Signal Transduction; Sirolimus; Skeletal Muscle; Stress; Testing; Therapeutic; Time; Tissues; Translational Regulation; Translations; Untranslated Regions; Up-Regulation; age related; analog; clinically relevant; detection of nutrient; dietary restriction; frailty; genome-wide analysis; inhibitor; innovation; mRNA Translation; muscle form; novel therapeutic intervention; physical inactivity; preservation; protein degradation; protein folding; response; tissue culture; tool; transcription factor; translational diagnostics

PROJECT SUMMARY Dietary restriction (DR) without malnutrition protects against age-related decline. Part of the response to DR involves restricting and redirecting translation to promote survival. On its own, genetically restricting translation increases lifespan and resistance to cellular stress, but little is known about the downstream mechanisms of regulation. The conserved nutrient sensing pathway governed by the target of rapamycin (TOR) positively regulates translation through the cap-binding complex (CBC) when nutrients are plentiful. We recently reported that restricting CBC activity increases survival during protein unfolding stress by upregulating the heat shock response (HSR), which maintains cellular health by regulating protein folding and turnover. Activation of the HSR involves upregulation of genes controlled by the transcription factor HSF1. One of these genes encodes the chaperone HSP90, which inhibits HSF1 at the protein level in a negative feedback loop. HSP90 translation and protein levels are downregulated during CBC restriction in C. elegans as well as during TOR inhibition in mouse tissue culture. We discovered that DR involving food dilution similarly suppresses synthesis of HSP90 relative to other cellular proteins. The HSR is universally recognized as critical to adaptation and survival, but the precise nature of its relationship to DR has been elusive. Translational regulation of HSP90 may act as a circuit in adaptation to DR involving the HSR. Our preliminary studies also show that increased survival to unfolded protein stress is driven by restricting the CBC in neurons or germ cells, which also limits reproduction. Interestingly, low CBC in these tissues upregulates the only Myogenic Response Factor (MRF) in C. elegans, HLH-1, which activates genes encoding structural components and chaperones in body muscle, the analog of skeletal muscle. Surprisingly, low CBC in muscle does not upregulate HLH-1 or provide robust protection from unfolded protein stress in that tissue but does increase reproduction. We propose that muscle is protected during DR to preserve function required for foraging and that low translation in muscle is a signal of inactivity associated with nutrient abundance. We will determine how low CBC activity associated with DR influences the HSR in different tissues and whether physical inactivity recapitulates the effects of low translation with respect to reproduction. We will also investigate the relationship between CBC activity and myogenic expression changes with respect to body muscle function, integrity, protection from protein unfolding stress, and lifespan. Finally, we will test the role of HSP90 in DR responses and in coordinating cross-talk between different tissues.

项目总结 没有营养不良的饮食限制(DR)可以防止年龄相关的下降。回应的一部分 DR涉及限制和重定向翻译以促进生存。它本身，基因上的限制 翻译可以延长寿命和抵抗细胞压力，但对下游基因知之甚少 监管机制。雷帕霉素靶标调控的保守营养传感途径 当营养充足时，(Tor)通过帽结合复合体(CBC)积极调节翻译。 我们最近报道，限制CBC活性通过以下方式提高蛋白质去折叠应激期间的存活率 上调热休克反应(HSR)，通过调节蛋白质折叠和 营业额。HSR的激活涉及转录因子HSF1控制的基因上调。一 这些基因中的一个编码伴侣HSP90，它在蛋白质水平上负反馈地抑制HSF1 循环播放。线虫在CBC限制期间HSP90翻译和蛋白质水平下调 在小鼠组织培养中抑制TOR。我们发现DR与食物稀释的作用类似 相对于其他细胞蛋白抑制HSP90的合成。高铁是举世公认的关键 与适应和生存有关，但它与DR之间的确切关系一直难以捉摸。翻译 HSP90的调节可能在参与HSR的DR适应中起回路作用。我们的初步研究也 显示对未折叠蛋白应激的存活率增加是通过限制神经元或生殖细胞中的CBC来驱动的 细胞，这也限制了生殖。有趣的是，这些组织中的低CBC上调了唯一的肌源性 线虫中的反应因子(MRF)，HLH-1，它激活编码结构组件和 身体肌肉中的伴侣蛋白，类似于骨骼肌。令人惊讶的是，肌肉中的低CBC并非如此 上调HLH-1或对组织中未折叠蛋白质应激提供强有力的保护，但确实会增加 繁殖。我们认为，肌肉在DR期间受到保护，以保留觅食所需的功能和 肌肉中的低转译是与营养丰富相关的不活动的信号。我们将决定 与DR相关的CBC活性降低如何影响不同组织中的HSR，以及 不活跃概括了低翻译对生殖的影响。我们还将调查 CBC活性与肌源性表达变化对人体肌肉功能的影响 完整性、不受蛋白质展开压力的保护和寿命。最后，我们将测试HSP90在DR中的作用。 反应和协调不同组织之间的串扰。