Genome wide association analysis with Drosophila to discover how metformin effects longevity

与果蝇的全基因组关联分析，以发现二甲双胍如何影响长寿

• 批准号: 10645126
• 负责人: MARC TATAR
• 金额: $ 39.88万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645126
• 关键词: Acceleration; Adult; Affect; Aging; Animal Model; Bioinformatics; Biological Models; Candidate Disease Gene; Complex; Complex Genetic Trait; Data; Data Analyses; Diet; Dissection; Dose; Drosophila genome; Drosophila genus; Experimental Genetics; Failure; Gene Expression; Gene Order; Genes; Genetic; Genetic Epistasis; Genetic Variation; Genetic study; Genomics; Human; Longevity; Mammals; Maps; Meta-Analysis; Metformin; Methods; Molecular; Mus; Orthologous Gene; Pathway interactions; Positioning Attribute; RNA Interference; Regulation; Series; Site; Survival Analysis; Testing; Translating; Variant; Work; age related; analytical method; cohort; experience; fly; genome wide association study; hazard; innovation; knock-down; mortality; novel strategies; reference genome; response; segregation; semiparametric; sex; success; trait; validation studies

Summary Drosophila can be used to discover the underlying molecular mechanisms by which metformin effects lifespan. From 112 tested cohorts, we found metformin can extend fly lifespan as much as 30% but in other conditions the compound equally reduced lifespan. Here we propose to identify genetic factors that contribute to this variation. We will conduct a genome wide association (GWA) analysis with Drosophila, combined with emerging bioinformatic analytics and molecular validation studies. We propose as well, an innovative approach to bridge Drosophila analysis to humans and mice by mapping response SNPs of the fly onto orthologous gene expression data from mammals. We will combine these approaches to resolve how metformin affects aging, and through which pathways it positively or negatively modulates lifespan.

概括 果蝇可用于发现二甲双胍的潜在分子机制 影响寿命。从 112 个测试组中，我们发现二甲双胍可以延长果蝇的寿命 为 30%，但在其他条件下，该化合物同样会缩短使用寿命。在此我们建议 确定导致这种变异的遗传因素。我们将进行全基因组研究 与果蝇的关联（GWA）分析，结合新兴的生物信息分析 和分子验证研究。我们还提出了一种创新的方法来桥接 通过将果蝇的响应 SNP 映射到直系同源上，对果蝇进行人类和小鼠分析 来自哺乳动物的基因表达数据。我们将结合这些方法来解决如何 二甲双胍影响衰老，以及它通过哪些途径进行积极或消极的调节 寿命。