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: 10153619
• 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/10153619
• 关键词: Address; Age; Aging; Alzheimer' s Disease; Binding; Binding Proteins; Biochemistry; Caenorhabditis elegans; Cell physiology; Cellular Stress; Complex; Data; Development; Diagnostic; Feedback; Fertility; Food; Gap Junctions; Genes; Genetic; Genetic Transcription; Genetic Translation; 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; 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; Structure; 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/antagonist; innovation; muscle form; novel therapeutic intervention; physical inactivity; preservation; protein degradation; protein folding; response; tissue culture; tool; transcription factor

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.

项目摘要 没有营养不良的饮食限制（DR）可以防止与年龄相关的下降。部分回应 DR涉及限制和重定向翻译以促进存活。就其本身而言， 翻译增加了寿命和对细胞应激的抵抗力，但对下游的翻译知之甚少。 监管机制。以雷帕霉素为靶点的保守的营养感受途径 (TOR)当营养丰富时，通过帽结合复合物（CBC）积极调节翻译。 我们最近报道，限制CBC活性可以通过以下方式增加蛋白质解折叠应激期间的存活率： 上调热休克反应（HSR），其通过调节蛋白质折叠来维持细胞健康， 周转HSR的激活涉及由转录因子HSF 1控制的基因的上调。一 其中1个基因编码HSP 90蛋白伴侣，HSP 90在蛋白水平上以负反馈方式抑制HSF 1 循环.在C.优雅的人以及 在小鼠组织培养中抑制TOR期间。我们发现，涉及食物稀释的DR类似于 相对于其他细胞蛋白，抑制HSP 90的合成。高铁是公认的关键 适应和生存，但它与DR的关系的确切性质一直难以捉摸。平移 HSP 90的调节可能作为一个电路，在适应DR涉及HSR。我们的初步研究还 显示未折叠蛋白应激的存活率增加是由限制神经元或胚芽中的CBC驱动的， 细胞，这也限制了繁殖。有趣的是，这些组织中的低CBC上调了唯一的肌源性 响应因子（MRF）（C）。elegans，HLH-1，它激活编码结构成分的基因， 身体肌肉中的伴侣，骨骼肌的类似物。令人惊讶的是，肌肉中的低CBC不会 上调HLH-1或提供对组织中未折叠蛋白质应激的强力保护， 生殖我们建议在DR期间保护肌肉以保留觅食所需的功能， 肌肉中的低翻译是与营养丰富相关的不活动的信号。我们将确定 与DR相关的低CBC活性如何影响不同组织中的HSR，以及 不活动概括了低翻译对繁殖的影响。我们还将调查 CBC活性与身体肌肉功能相关的肌源性表达变化之间的关系， 完整性、保护蛋白质不受解折叠应力和寿命。最后，我们将测试HSP 90在DR中的作用。 响应和协调不同组织之间的串扰。