IDENTIFYING MICROBIAL MECHANISMS THAT REGULATE ANIMAL INSULIN SIGNALING

项目总结 胰岛素抵抗和2型糖尿病影响了近10%的人口，而且还在上升。最近的证据 这表明人类肠道细菌可以调节胰岛素的释放，这意味着微生物 影响胰岛素信号转导的新机制或因素。鉴定微生物和新细菌 在哺乳动物体内调节动物胰岛素释放的机制是非常具有挑战性的，因为 哺乳动物肠道微生物区系中广泛的微生物多样性，而且因为驻留的微生物 抵抗人工给药的分离物的定植。我已经通过开发一种 用于鉴定体内调节胰岛素信号的细菌分离株的新型高通量线虫模型， 并(首次)证明了环境细菌中含有以前未被发现的、新颖的 调节动物胰岛素抵抗的机制或因素。在这个变革性的项目中，我将执行 首次大规模筛选修改动物胰岛素信号的生物活性细菌；使用转座子 突变以确定那些负责调节胰岛素信号的细菌基因或因素；以及工程 至少一种表达细菌胰岛素调节系统或因子的人类益生菌菌株。总而言之，这是 该项目将对修改动物胰岛素信号的细菌类型产生新的见解；其机制 细菌已经进化到这一点；并为该领域提供了根本上的新方向和战略 缓解人类现存最常见和最具影响力的疾病之一。

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.