IDENTIFYING MICROBIAL MECHANISMS THAT REGULATE ANIMAL INSULIN SIGNALING

项目摘要 胰岛素抵抗和2型糖尿病影响了近10%的人口，并且正在上升。最近的证据 表明人类肠道细菌可以调节胰岛素的释放，这意味着微生物具有 影响胰岛素信号传导的新机制或因素。鉴定微生物和新细菌 体内调节动物胰岛素释放的机制在哺乳动物中是非常具有挑战性的， 哺乳动物肠道微生物群中广泛的微生物多样性，并且由于常驻微生物 对人工管理的隔离物的殖民化有抵抗力。我克服了这些局限性， 新型高通量C.用于鉴定调节体内胰岛素信号传导的细菌分离物的Elegans模型， 并证明（第一次）环境细菌含有以前未发现的，新的 调节动物胰岛素抵抗的机制或因子。在这个变革性的项目中，我将执行 有史以来第一次，大规模筛选生物活性细菌，修改动物胰岛素信号;使用转座子 诱变以鉴定负责调节胰岛素信号传导的那些细菌基因或因子;和 至少一种表达细菌胰岛素调节系统或因子的人益生菌菌株。总的来说，这 该项目将产生新的见解类型的细菌，修改动物胰岛素信号;机制 细菌已经进化到这样做;并为该领域提供了全新的方向和策略， 缓解现存最常见和最具影响力的人类病理之一。

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.