Gary Ruvkun

In my lab I use C. elegans molecular genetics and genomics to study problems in developmental biology and physiology. I have have studied the pathways by which microRNAs and other small RNAs regulate the translation of messenger RNAs as well as other gene expression mechanisms. My lab is now using functional genomic and genetic strategies to systematically discover the components of the RNAi and microRNA pathways in C. elegans. Using full genome RNAi screens to reveal RNAi and miRNA pathway components, they have recently identified many genes that positively or negatively regulate RNAi and microRNA pathways. Most of the genes identified in these screens are conserved across eukaryotic phylogeny, suggesting universality of these small RNA pathways. Some of these components may be developed as drug targets to enhance RNAi in mammals, a technical improvement that may be necessary to elevate a laboratory tool to a therapeutic modality. Over the past decade, my lab discovered that like mammals, C. elegans uses an insulin signaling pathway to control its metabolism and longevity. Their molecular genetic analysis revealed an insulin-like receptor signaling cascade to the DAF-16/FoxO transcription factor. This analysis has revealed conservation of molecular mechanisms at many steps in the pathway, suggesting that insulin regulation of longevity and metabolism is ancient and universal. Our lab then showed that insulin signaling in the nervous system is key to lifespan. Functional genomic analyses using RNAi libraries of every C. elegans gene now allows a systematic study of metabolism and aging. Our lab has surveyed the 18,000 genes for their action in regulation of longevity, fat deposition, and molting. This analysis gives a global view of the molecular machines that operate in these pathways. 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 is emerging from these studies.