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

描述（由申请人提供）：饮食限制（DR），减少饮食中的营养物质，为延长寿命和减缓酵母、蠕虫、果蝇和啮齿动物等多种物种的年龄相关疾病提供了最有效的方法。鉴于DR的普遍保护作用，研究其分子机制将促进对各种人类年龄相关疾病发病机制的更好理解。这反过来将有助于促进这些疾病的治疗方法的发展。由于无脊椎动物模型的寿命短，易于遗传操作，因此它们仍然是了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护，在模式生物中的研究可能会对我们理解DR. Kapahi实验室延长寿命的生物学机制做出最大的贡献。先前确定了TOR（雷帕霉素靶点）通路作为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测中起着保守的作用。最近，Kapahi实验室表明，调节mRNA翻译是TOR通路下游的一个关键机制，该通路通过饮食限制决定寿命延长。该实验室已经建立了一种翻译谱分析方法，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调节DR代谢的差异翻译基因，其中一些是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。在该提案中，我们旨在通过以下目的来检查mRNA翻译中的组织特异性变化在介导DR延长寿命中的作用：1）检查DR后的组织特异性全基因组翻译变化和2）表征差异翻译基因对各种年龄相关功能下降的影响。这一建议将创建工具，允许组织特异性评估mRNA的翻译状态在D。黑腹菌该提案将严格审查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性下降中发挥作用。复杂的身体结构，相对较短的寿命和强大的遗传工具，允许快速发现与表型相关的新基因是D的一些优势。这使它非常适合这项提议。GAL 4-UAS系统操纵基因表达的可用性将允许全面测试组织特异性基因表达对给定表型的作用。此外，有一组丰富的生理和行为表型，可以在D。黑胃动物，包括代谢，身体组成，肾功能，记忆和流动性的变化。这使得D。黑腹肌是研究组织特异性变化对健康寿命和衰老的功能意义的理想系统。 公共卫生相关性：饮食限制是各种物种中延长寿命的最强大的环境方法，并已被证明可以预防各种与年龄相关的疾病，包括糖尿病，癌症和神经退行性疾病。本研究以果蝇为研究对象，探讨组织特异性mRNA翻译变化介导限食延长寿命效应的机制。我们的发现将对理解营养在人类衰老和与年龄相关的疾病中的作用产生重大影响。

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.