The Role of Insulin Signaling in Developmental Ethanol Toxicity

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Project Summary: Developmental ethanol exposure causes a variety of deleterious phenotypes in taxa from insects to humans, including growth deficiency, developmental mortality, metabolic changes, intellectual disabilities, and behavior problems. In humans, these symptoms are collectively described as fetal alcohol spectrum disorder (FASD). Though epidemiological evidence suggests a minimum of 80,000 new cases of FASD every year in the United States alone, there is currently no approved biological treatment for FASD. Ethanol exposure is especially damaging to the developing nervous system and this has long-term consequences on adult behavior. The toxicity of developmental ethanol exposure has been attributed to numerous mechanisms, including ethanol metabolism and related oxidative stress, neuronal cell loss, and inhibition of growth factors and/or their signal transduction pathways. In particular, insulin and insulin-like growth factor (IGF) signaling is a universal target of developmental ethanol exposure. In mammals, the resulting insulin resistance leads to sensitivity to metabolic syndrome, which can be exacerbated by a high-fat diet. The goal of our research is to use the genetically amenable model organism Drosophila melanogaster to identify the molecular targets of developmental ethanol exposure, to understand how disruption of those targets leads to the deleterious phenotypes associated with developmental ethanol, and to test interventions that may one day lead to treatments for FASD in humans. Drosophila melanogaster, the common fruit fly, has been used extensively in biological research, particularly in genetics and development. Drosophila are particularly amenable to sophisticated genetic analyses, including genomic approaches, reverse and molecular genetics, and traditional forward genetic screens. Moreover, over a century of research has led to an extensive collection of genomic, molecular, genetic, and pharmacological tools, making Drosophila tremendously powerful in the elucidation of gene function. We have established and developed a genetic model of FASD in flies, and have used this model to show that insulin signaling is disrupted by developmental ethanol exposure, and that flies exposed to ethanol during development have phenotypes consistent with metabolic syndrome. We also have the first evidence that dietary changes may ameliorate the developmental effects of ethanol on metabolism. Finally, we discovered that developmental exposure to alcohol causes feeding deficits similar to those seen in mammals exposed to ethanol, and we have evidence implicating altered insulin signaling in this phenotype as well. Our research will further elucidate the role of insulin signaling in the development of FASD, by investigating the interaction between insulin signaling, diet, and predisposition to metabolic syndrome, as well as testing possible treatments for DAE-induced metabolic syndrome. In addition, we propose to further elucidate the molecular and neuronal signaling pathways that lead to changes in feeding behavior triggered by DAE. Our specific aims are: 1) to determine how diet and insulin signaling interact to mediate the toxicity of developmental ethanol exposure, and 2) to investigate the role of insulin signaling in the abnormal feeding behaviors that result from DAE.