The Ruvkun lab has explored two major themes: regulation by microRNA genes and other small RNAs, and control of longevity and metabolism by insulin and other endocrine pathways. Thousands of miRNAs have been discovered and are now implicated in control of gene expression of across eukaryotic phylogeny.
Saturation genetic analysis of the miRNA and RNAi pathways by the Ruvkun lab has revealed many of the protein cofactors that may mediate steps in how miRNAs and siRNAs engage their targets. These miRNA pathway protein cofactors could mediate steps in the recognition of the miRNA::mRNA RNA duplex to down-regulate translation. There is also increasing evidence of a cell biology of RNA regulation, so a more complex choreography is likely. The Ruvkun lab also discovered that there is complex negative regulation of RNAi and competing small RNA pathways. In addition to revealing fundamental regulatory axes in biology, 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.
The Ruvkun lab discovered many elements of the insulin-like signaling pathway controls C. elegans metabolism and longevity. Saturation genetic analysis of the pathway in the Ruvkun laboratory identified most of the signaling components, including daf-16, a Forkhead transcription factor that illuminated the function of the mammalian FoxO transcription factors, now intensively studied as insulin signaling transcriptional outputs. Recent insulin signaling mutant analyses in mouse and humans have validated the generality of these discoveries to other animals. These findings are also important for the eventual treatment of diabetes, a disease of insulin signaling. Dr. Ruvkun’s lab has also used full genome RNAi libraries to explore the comprehensive set of genes that regulate aging and metabolism. Many of these genes are broadly conserved in animal phylogeny and are likely to reveal the neuroendocrine system that assesses and regulates energy stores and assigns metabolic pathways based on that status. This study revealed other arrest points induced by gene inactivations that are as highly regulated and as key to lifespan regulation as the insulin regulated arrest point. Many of the gene inactivations that cause increased survival of arrested larvae encode the core conserved elements of cells that are targeted by antibiotics, which are produced by a wide range of fungi and microbes that animals encounter. Inactivation of these core genes may induce an endocrine state of drug detoxification and longevity induction. This xenobiotic regulatory axis has important and surprising implications for human health: the endocrine states that are normally induced by poisons and variation in the conserved detoxification response pathway may underlie diseases not normally thought of as xenobiotic response dysregulations.