We respectfully submit this proposal pursuant to Notice NOT-OD-09-058, NIH announces the Availability of Recovery Act Funds for Competitive Revision. Aging remains one of the most complex biological mysteries of modern bioscience. This proposal examines how modulation of protein translation plays a key role in determining lifespan. This hypothesis is based on findings from various groups including ours that inhibition of a number of genes that regulate mRNA translation extend lifespan. Inhibition of ifg-1 (worm homologue of eIF4G, a scaffold protein for the eIF4F complex that initiates protein synthesis) during adulthood is sufficient for lifespan extension, but its downregulation during development leads to larval arrest (Pan et al., 2007). Inhibition of ifg-1 also results in increased stress resistance and decreased fecundity, suggesting that modulating mRNA translation mediates tradeoffs between somatic maintenance and growth that influence longevity. These results are consistent with the antagonistic pleiotropy theory of aging, which proposes that genes with essential roles during development may negatively influence adult lifespan (Williams, 1957). We have established the methodology proposed in the parent award to this application to undertake translation profiling that can identify changes mRNA translation in C. elegans. Using this approach we have identified differentially translated genes upon inhibition of ifg-1. We observe that levels of ifg-1 are reduced under conditions of nutrient limitation and that inhibition of ifg-1 leads to an upregulation of stress response genes by a posttranscriptional mechanism of gene regulation. We hypothesize that ifg-1 acts as a switch in regulating mRNA translation between development and somatic maintenance, providing a novel post transcriptional mechanism to mediate antagonistic pleiotropic effects that influence aging. In light of our findings we propose the following Specific Aims: 1) Investigating mechanisms of posttranscriptional gene expression by creating translational fusion GFP reporters for differentially translated genes. 2) Translational profiling under nutrient limitation stress. 3) Characterization of genes that are differentially translated under nutrient limitation stress. This proposal aims to test a novel hypothesis that mRNA translation modulates lifespan and examines its role under nutrient limiting conditions including dietary restriction which is one of the most robust methods to extend lifespan and slow age-related diseases. This proposal will develop methodologies and create tools to examine mechanisms of posttranscriptional regulation of gene expression. Aging is the single largest risk factor for a number of diseases in developed countries. Findings from this proposal will have a significant impact on understanding the basic mechanisms of aging and developing therapeutics to slow various age- related diseases including cancer, diabetes and neurodegeneration. In addition to providing job opportunities and open new areas of research this research hopes to lead to long-term benefits of the American Recovery and Reinvestment Act (ARRA).
Posttranscriptional regulation of gene expression has been shown to play an important role in aging and various age related diseases including diabetes, cancer and neurodegeneration. This proposal investigates the fundamental mechanisms of posttranscriptional regulation of gene expression using C. elegans. This proposal will create novel tools that can be used by the scientific community at large to explore the basic mechanisms of regulation of mRNA translation. Given the similarity of posttranscriptional regulation of gene expression across different species our findings will have a significant effect on understanding of aging and age related diseases in humans.
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