PROJECT SUMMARY Insulin resistance and Type 2 diabetes affect nearly 10% of the population, and are on the rise. Recent evidence suggests that human intestinal bacteria can regulate insulin release, which implies that microorganisms harbor novel mechanisms or factors that influence insulin signaling. Identifying microorganisms and novel bacterial mechanisms of modulating animal insulin release in vivo is very challenging in mammals because of the extensive microbial diversity in the mammalian intestinal microbiota, and because resident microorganisms are resistant to colonization by artificially administered isolates. I have overcome these limitations by developing a novel, high-throughput C. elegans model for identifying bacterial isolates that regulate in vivo insulin signaling, and demonstrated (for the first time) that environmental bacteria contain previously undiscovered, novel mechanisms or factors for regulating animal insulin resistance. In this transformative project, I will perform the first-ever, large-scale screen for bioactive bacteria that modify animal insulin signaling; use transposon mutagenesis to identify those bacterial genes or factors responsible for regulating insulin signaling; and engineer at least one human probiotic strain to express a bacterial insulin-regulating system or factor. Taken together, this project will generate new insights into the types of bacteria that modify animal insulin signaling; the mechanisms bacteria have evolved to do so; and provide the field with fundamentally new directions and strategies for alleviating one of the most common and impactful human pathologies in existence.

PROJECT NARRATIVE Insulin resistance and Type 2 diabetes are among the most common and impactful human diseases in existence, and are on the rise. I discovered that environmental bacteria have novel mechanisms or factors that can regulate animal insulin signaling. To launch my independent research career, I will perform the first-ever, large-scale screen for bioactive bacteria that modify animal insulin signaling and identify the mechanisms bacteria have evolved to do so, which will provide the field with a fundamentally new strategy to identify novel therapies or treatments for insulin resistance.