MicroRNAs (miRNAs) constitute a novel class of gene regulatory elements with important roles in the control of gene expression and development in plants and animals. miRNAs are endogenous, small non-coding RNAs which inhibit gene expression by base pairing with target genes and silencing their expression via mechanisms which are still being elucidated. Although highly abundant and predicted to target a wide proportion of genes in higher organisms, miRNAs have so far only been implicated in handful of biological roles. The function of the vast majority of miRNAs remains a mystery. Two founding members of the miRNA family, lin-4 and let-7, were first identified in the heterochronic pathway of C. elegans, which regulates the timing of larval development in the nematode. Both miRNAs have more recently been implicated in other biological areas, such as cancer and life span. Recent work has demonstrated that mutations to lin-4 and its target lin-14 significantly affect the lifespan of C. elegans. In addition, microarray analysis in C. elegans has revealed dynamic miRNA expression changes during aging. These observations suggest that miRNAs may function in pathways that impact life span. This proposal seeks to study the role of known miRNAs in aging, the identification of novel miRNAs in aged animals, and the genetic mechanisms underlying their function. In order to achieve these objectives, miRNAs will first be cloned from aged populations of C. elegans and from mutant worms that exhibit altered lifespan. The focus on enriched population of aged animals will allow the characterization of potential roles for new miRNAs in lifespan. Newly identified miRNAs as well as previously characterized heterochronic genes will then be mutated and assayed for lifespan effects in adult worms. We predict that yet unidentified miRNAs may modulate life span or serve as biomarkers of diseases of aging. Finally, in order to understand the genetic mechanisms underlying their role in aging, the downstream effects of mutations to these miRNAs will be studied by a variety of techniques including GFP:fusion expression analysis and epistastic relationship to genes in known life span pathways. Relevance: Understanding the biological mechanisms underlying aging is a key goal of current medical research. The short life span of the nematode C. elegans makes it the organism of choice in the study of aging. MicroRNAs, a novel class of regulatory elements first identified in C. elegans, have now been shown to modulate life span. We seek to identify new miRNAs with a role in aging and to study their function. Given the high conservation of microRNAs across species, findings from this research may lead to new biomarkers of diseases of aging and will inform on our understanding of aging in higher organisms and humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
4F32AG030851-03
Application #
8140626
Study Section
Special Emphasis Panel (ZRG1-F08-A (20))
Program Officer
Guo, Max
Project Start
2009-08-01
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
3
Fiscal Year
2011
Total Cost
$63,182
Indirect Cost
Name
Yale University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
de Lencastre, Alexandre; Slack, Frank (2015) Discovery of Novel microRNAs in Aging Caenorhabditis elegans. Methods Mol Biol 1343:235-48
Smith-Vikos, Thalyana; de Lencastre, Alexandre; Inukai, Sachi et al. (2014) MicroRNAs mediate dietary-restriction-induced longevity through PHA-4/FOXA and SKN-1/Nrf transcription factors. Curr Biol 24:2238-46
Inukai, Sachi; de Lencastre, Alexandre; Turner, Michael et al. (2012) Novel microRNAs differentially expressed during aging in the mouse brain. PLoS One 7:e40028
de Lencastre, Alexandre; Pincus, Zachary; Zhou, Katherine et al. (2010) MicroRNAs both promote and antagonize longevity in C. elegans. Curr Biol 20:2159-68