Role of mRNA translation in the effects of dietary restriction on lifespan

mRNA 翻译在饮食限制对寿命影响中的作用

• 批准号: 7994691
• 负责人: Pankaj Kapahi
• 金额: $ 38.8万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7994691
• 关键词: 5' Untranslated Regions; Advanced Development; Affinity Chromatography; Age; Aging; Animal Model; Animals; Behavioral; Binding; Biochemistry; Bioinformatics; Biological; Biological Process; Body Composition; Candidate Disease Gene; Cell Communication; Cells; Code; Complex; Density Gradient Centrifugation; Diabetes Mellitus; Diet; Discipline; Disease; Drosophila genus; Elements; Embryo; Fatty acid glycerol esters; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic Translation; Genome; Genomics; Goals; Human; Individual; Invertebrates; Investigation; Kidney; Laboratories; Length; Link; Longevity; Luciferases; Malignant Neoplasms; Malpighian Tubules; Masks; Measures; Mediating; Memory; Metabolism; Methods; Mitochondria; Modeling; Molecular; Muscle; Nerve Degeneration; Neurons; Nuclear; Nutrient; Output; Pathogenesis; Pathway interactions; Phenotype; Physiological; Physiology; Play; Polyribosomes; RNA Sequences; Renal function; Reporter; Research; Ribosomal Proteins; Ribosomes; Rodent; Role; Signal Pathway; Sirolimus; Structure; System; Testing; Tissue-Specific Gene Expression; Tissues; Translating; Translations; Untranslated Regions; Work; Yeasts; age related; base; cell type; detection of nutrient; dietary restriction; dopaminergic neuron; fly; functional decline; genetic manipulation; genome wide association study; genome-wide; human disease; interdisciplinary approach; nutrition; promoter; protective effect; public health relevance; response; therapeutic target; tool

DESCRIPTION (provided by applicant): Dietary restriction (DR), a reduction of nutrients in the diet, provides the most robust method of lifespan extension and slowing of age-related diseases in species as diverse as yeast, worms, fruit flies, and rodents. Given the universally protective effects of DR, investigating its molecular mechanisms will promote a greater understanding of the pathogenesis of various human age-related diseases. This will in turn help advance the development of therapies for these disorders. Due to their short life spans and the ease of genetic manipulation, invertebrate models continue to be useful as models for understanding human diseases and in providing therapeutic targets. Given the conservation of biological processes and signaling pathways, studies in model organisms are likely to make the greatest contributions to our understanding of biological mechanisms of lifespan extension by DR. The Kapahi laboratory previously identified the TOR (target of rapamycin) pathway as a critical regulator of nutrient modulated lifespan changes in flies. This genetic pathway plays a conserved role in sensing nutrients in yeast, worms, flies and humans. Recently, the Kapahi laboratory showed that modulating mRNA translation is a key mechanism downstream of the TOR pathway that determines lifespan extension by dietary restriction. The lab has established a method for translational profiling that measures the mRNA translation state at the genome wide level. The lab has identified differentially translated genes that regulate metabolism upon DR, some of which are required for lifespan extension by DR. However, the role of tissue-specific changes and their respective contribution to extending lifespan upon DR remains unknown. In this proposal we aim to examine the role of tissue-specific changes in mRNA translation in mediating lifespan extension by DR by undertaking the following aims: 1) To examine tissue- specific genome-wide translation changes upon DR and 2) To characterize the effects of differentially translated genes on various age-related functional declines. This proposal will create tools that allow tissue specific assessment of mRNA translation state in D. melanogaster. The proposal will critically examine whether tissue-specific changes in mRNA translation and transcription play a role in age-related decline in various functions. The complex body plan, relatively short life span and the powerful genetic tools that allow the rapid discovery of new genes associated with a phenotype are some of the strengths of D. melanogaster that make it ideal for this proposal. The availability of the GAL4-UAS system to manipulate gene expression will allow comprehensive testing of the role of tissue-specific gene expression on given phenotypes. Further, there is a rich set of physiological and behavioral phenotypes that can be examined in D. melanogaster, including changes in metabolism, body composition, kidney function, memory, and mobility. Together this makes D. melanogaster an ideal system to examine the functional significance of tissue-specific changes on healthspan and aging. PUBLIC HEALTH RELEVANCE: Dietary restriction is the most robust environmental method of lifespan extension in various species and has been shown to protect against various age related diseases including diabetes, cancer and neurodegeneration. This proposal investigates the mechanism by which tissue specific changes in mRNA translation mediates the lifespan extension effects by dietary restriction using Drosophila. Our findings will have a significant effect on understanding the role of nutrition in aging and age related diseases in humans.

描述（由申请人提供）：饮食限制（DR），即减少饮食中的营养，为酵母、蠕虫、果蝇和啮齿动物等多种物种提供了最有效的延长寿命和减缓与年龄相关疾病的方法。鉴于DR具有普遍的保护作用，研究其分子机制将有助于更好地了解各种人类年龄相关疾病的发病机制。这反过来将有助于促进这些疾病的治疗方法的发展。由于它们的寿命短和易于遗传操作，无脊椎动物模型仍然是理解人类疾病和提供治疗靶点的有用模型。考虑到生物过程和信号通路的保守性，对模式生物的研究可能会对我们理解DR.延长寿命的生物学机制做出最大贡献。Kapahi实验室先前确定了TOR（雷帕霉素靶点）途径是果蝇营养调节寿命变化的关键调节因子。这种遗传途径在酵母、蠕虫、苍蝇和人类的营养感知中起保守作用。最近，Kapahi实验室发现，调节mRNA翻译是TOR通路下游的一个关键机制，通过饮食限制来决定寿命延长。该实验室已经建立了一种翻译分析方法，可以在全基因组水平上测量mRNA的翻译状态。该实验室已经确定了DR时调节代谢的差异翻译基因，其中一些基因是DR延长寿命所必需的。然而，组织特异性变化的作用及其各自对DR延长寿命的贡献仍然未知。在本提案中，我们旨在通过以下目的来研究mRNA翻译的组织特异性变化在DR中介导寿命延长的作用：1)研究DR中组织特异性的全基因组翻译变化；2)表征差异翻译基因对各种年龄相关功能衰退的影响。该建议将创建工具，允许组织特异性评估mRNA翻译状态的D. melanogaster。该提案将严格检查mRNA翻译和转录的组织特异性变化是否在各种功能的年龄相关衰退中发挥作用。复杂的身体结构，相对较短的寿命和强大的遗传工具，使得快速发现与表现型相关的新基因成为黑腹龙的优势，使其成为这项提议的理想选择。GAL4-UAS系统操纵基因表达的可用性将允许对组织特异性基因表达在给定表型上的作用进行全面测试。此外，在黑腹龙身上还可以检测到一系列丰富的生理和行为表型，包括代谢、身体成分、肾功能、记忆和活动能力的变化。总之，这使得D. melanogaster成为一个理想的系统来检查组织特异性变化对健康和衰老的功能意义。