Starvation resistance and resilience of metabolic dysfunction in cavefish - Project Summary The overarching goal is to understand the complex genetic network regulating energy metabolism. This is a critically important problem from the standpoint of human health, and a great deal has already been learned through previous physiological and genetic studies of normal and disease conditions, primarily in humans and rodents. Many of these studies have taken advantage of patients or laboratory animals with extremely impaired metabolic responses. In these cases, errors in metabolic pathways result in severe deleterious consequences, leading to morbidity and mortality. In nature, however, there is a second kind of extreme variation: there are many cases where animals have adapted to extreme environments or extreme lifestyles through changes in metabolic regulation. In these instances, the metabolic changes are adaptive, not pathological, meaning they occur in such a way that the effects are not deleterious and/or other physiological changes occur to compensate for any detrimental consequences. In principle, this provides an opportunity for identifying resilience mechanisms that may have escaped notice through study of the circuits disrupted in disease. However, to fully harness this natural variation for gene discovery, one wants to be able to compare metabolic regulation in such animals with related organisms that have not undergone such extreme adaptation. Yet, in many cases there is no closely related animal with a more “normal” metabolism for comparison. An important exception is the cave-dwelling Mexican cave tetra, Astyanax mexicanus, which thrives under essentially starvation conditions, and its river cousins who are of the same species. Together they offer a unique and exciting opportunity to examine the metabolic adaption to an extreme living condition in an organism ripe for genetic and genomic analysis. This proposal builds on published data showing that cavefish have evolved a dramatically altered metabolism, including accumulation of high body fat levels and fatty livers, insulin resistance and unstable blood glucose levels, without apparent adverse effects on their health. Use of state of the art genomic, genetic and gene editing technologies now offers the possibility of identifying signaling pathways that underlie starvation resistance and resilience mechanisms under extreme nutritional situations. The proposal leverages the practical advantages of the model system to be amenable to comparative approaches such as RNA-Seq, chromatin architecture analysis, mapping strategies such as QTL-analysis, gene modification techniques such as CRISPR/Cas9, and novel transgenic lines, all combined with its unique ecological adaptation scenario. This research proposal, therefore, aims to take advantage of this resource to understand more fully the metabolic changes that allow the cavefish to survive in their bleak environment and to start to dissect the regulatory changes that underlie the resilience mechanisms allowing these fish to tolerate what in most animals, including us humans, would be considered a disease.
