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

描述(申请人提供)：饮食限制(DR)，减少饮食中的营养物质，提供了最有力的方法来延长和减缓各种与年龄相关的疾病的寿命，如酵母、蠕虫、果蝇和啮齿动物。鉴于DR的普遍保护作用，研究其分子机制将有助于更好地了解人类各种与年龄相关的疾病的发病机制。这反过来将有助于推动这些疾病的治疗方法的发展。无脊椎动物模型由于寿命短和易于进行基因操作，继续被用作理解人类疾病和提供治疗靶点的模型。鉴于生物过程和信号通路的保守性，对模型生物的研究很可能对我们理解延长寿命的生物学机制做出最大贡献，Kapahi博士的实验室以前发现TOR(雷帕霉素的靶标)途径是营养调节果蝇寿命变化的关键调节因子。这种遗传途径在感知酵母、蠕虫、苍蝇和人类的营养方面起着保守的作用。最近，Kapahi实验室发现，调节mRNA翻译是TOR途径下游的一个关键机制，它决定了通过限制饮食来延长寿命。该实验室已经建立了一种翻译图谱的方法，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控DR新陈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对延长DR寿命的贡献仍不清楚。在这项建议中，我们旨在通过以下目的来研究组织特异性mRNA翻译变化在DR延长寿命中的作用：1)检测DR时组织特异性全基因组翻译变化；2)鉴定差异翻译基因对各种年龄相关功能下降的影响。这项提议将创建工具，允许组织特异性地评估黑腹金丝猴的mRNA翻译状态。该提案将严格检查组织特异性的mRNA翻译和转录变化是否在与年龄相关的各种功能下降中发挥作用。复杂的身体规划，相对较短的寿命，以及强大的基因工具，可以快速发现与表型相关的新基因，这些都是黑腹葡萄球菌的一些优势，使其成为这一提议的理想选择。GAL4-UAS系统可用于操纵基因表达，这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，还有一套丰富的生理和行为表型，可以在黑腹金龟身上检测到，包括新陈代谢、身体成分、肾功能、记忆力和移动性的变化。总而言之，这使得黑腹毛虫成为一种理想的系统，可以用来研究特定组织变化对健康寿命和衰老的功能意义。 公共卫生相关性：饮食限制是各种物种中最有力的延长寿命的环境方法，已被证明可以预防各种与年龄有关的疾病，包括糖尿病、癌症和神经退化。本研究以果蝇为研究对象，研究了果蝇体内组织特异性的mRNA翻译变化在饮食限制延长寿命中的作用机制。我们的发现将对理解营养在衰老和人类衰老相关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.