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: 10004550
• 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/10004550
• 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.

项目概要 没有营养不良的饮食限制（DR）可以防止与年龄相关的衰退。部分回应 DR 涉及限制和重定向翻译以促进生存。就其本身而言，基因限制 翻译可延长寿命并增强对细胞应激的抵抗力，但对其下游下游知之甚少 监管机制。雷帕霉素靶标控制的保守营养传感途径 当营养充足时，TOR（TOR）通过帽子结合复合物（CBC）积极调节翻译。 我们最近报道，限制 CBC 活性可通过以下方式提高蛋白质展开应激期间的存活率： 上调热休克反应 (HSR)，通过调节蛋白质折叠和维持细胞健康 周转。 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，它以负反馈方式在蛋白质水平上抑制 HSF1 环形。线虫 CBC 限制期间 HSP90 翻译和蛋白质水平下调 在小鼠组织培养中 TOR 抑制期间。我们发现 DR 也同样涉及食物稀释 相对于其他细胞蛋白，抑制 HSP90 的合成。高铁被普遍认为是至关重要的 适应和生存，但其与 DR 关系的确切性质一直难以捉摸。翻译性 HSP90 的调节可以充当适应涉及 HSR 的 DR 的电路。我们的初步研究还 研究表明，通过限制神经元或细菌中的 CBC 来提高对未折叠蛋白应激的存活率 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 线虫中的响应因子 (MRF)，HLH-1，可激活编码结构成分和 身体肌肉中的伴侣，类似于骨骼肌。令人惊讶的是，肌肉中的低 CBC 并没有 上调 HLH-1 或针对该组织中的未折叠蛋白应激提供强有力的保护，但确实会增加 生殖。我们建议在 DR 期间保护肌肉，以保留觅食和进食所需的功能。 肌肉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，以及身体是否 不活动概括了低翻译对复制的影响。我们还将调查 CBC 活性与肌原性表达变化之间的关系与身体肌肉功能有关， 完整性、免受蛋白质展开压力的保护和寿命。最后我们来测试一下HSP90在DR中的作用 反应并协调不同组织之间的串扰。