3D Tissue Models

Gary Ruvkun

TypeWhite Paper Summary

The Ruvkun lab uses C. elegans molecular genetics and genomics to study miRNA and RNAi pathways. Using genetic and RNA interference approaches, we have recently identified many genes that positively or negatively regulate RNAi and microRNA pathways. These genes reveal the trajectory of siRNAs and miRNAs as they target mRNAs, as well as components that may be developed as drug targets to enhance RNAi in mammals.

Over the past decade, the Ruvkun lab has discovered that like mammals, C. elegans uses an insulin signaling pathway to control its metabolism and longevity. This analysis has revealed striking congruence of molecular mechanisms at many steps in the pathway, suggesting that insulin regulation of longevity and metabolism is ancient and universal. The new genes of the insulin pathway that have emerged from these studies are conserved in animal phylogeny and represent new targets for diabetes drug development. Our finding that an insulin pathway regulates lifespan and metabolism immediately suggested a concordance with studies of mammalian lifespan: it is reminiscent of the increase in mouse and rat lifespan that is induced by low calorie diets, which reduce insulin levels.

Functional genomic analyses using RNAi libraries of every C. elegans gene now allows a systematic study of metabolism and aging. Our lab has surveyed 18,000 genes for their action in regulation of longevity, fat deposition, RNAi, and molting. This analysis gives a global view of the molecular machines that operate in these pathways. In the case of aging, it is now clear that insulin signaling is the most potent gene inactivation that can increase C. elegans lifespan, but about 100 other gene inactivations cause increases in lifespan. Current research in the Ruvkun lab attempts to weave these lists of aging regulatory genes into pathways that assess and regulate metabolic tempo and mode, repair and regeneration, and protective and degenerative pathways. Other gene inactivations perturb fat deposition without affecting lifespan and vice versa. These gene lists reveal the many steps in energy regulation, including metabolic enzymes that store and mobilize fat, as well as hormonal signals from fat stores to satiety centers in the brain. A neuroendocrinology of energy balance and longevity will emerge from these studies. Obesity is also a major health problem. Because 200 of the 400 C. elegans fat regulatory genes have human orthologs, new targets for the development of anti-obesity drugs may emerge from the C. elegans analysis.

We are developing protocols and instruments that use PCR primers corresponding to universal sequence elements of the 16S RNA gene to search for diverse microbes that may cause diseases unsuspected to be due to pathogens and microbes from extreme environments. One long term goal of this project is to send a robotic thermal cycler with these primers to Mars in search of microbial life that is ancestrally related to life on Earth.

Name:Gary Ruvkun
Organization:Harvard University

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