Discovery of GPCR-active natural products and their biosynthetic genes from the human associated bacteria

项目摘要：受人类微生物组启发的疗法的开发至少部分受到限制 由于我们对人类相关 (HA-) 细菌如何与其人类宿主沟通缺乏了解。 人类微生物组测序研究表明细菌种群变化之间存在很强的相关性 和人类健康。尽管存在这些相关性并且有证据将 HA 细菌与小鼠疾病联系起来， HA-细菌如何具体影响哺乳动物生理机能的机制细节在很大程度上仍然未知。在 在其他环境中，已知细菌严重依赖低分子量化合物（小分子 或天然产物）与其他生物体相互作用。同样，我们预计 HA 细菌可能会使用 小分子与人类宿主相互作用。越来越多的证据表明，尽管每个人 微生物组由复杂的细菌集合组成，物种数量少得多，但高度 普遍存在于大多数个体中。虽然我们并不确切知道是哪些 HA 细菌造成的 维持人类健康或引起疾病，我们假设这些产生的小分子 常见的HA-细菌可能在调节人体生理机能方面发挥重要作用。的 该提案的中心目标是筛选最常见的人类HA-产生的代谢物 细菌进行高通量 GPCR 活性测定，以鉴定 GPCR 活性小分子和生物合成 产生它们的基因簇。 GPCR 构成最大的真核跨膜受体家族。 众所周知，它们在人类生物学中发挥着多样化和深远的作用，并且容易受到小分子的调控。 分子。基于 GPCR 在化学信息转换中发挥如此广泛作用的事实 从环境到真核细胞的生物信号，我相信HA-细菌可能会影响宿主 通过产生与 GPCR 相互作用的小分子来调节生理学。该提案的两个目标 将导致 (1) HA 细菌编码代谢物的鉴定、分离和结构阐明 与不同的 GPCR 相互作用，以及 (2) 这些新颖的生物合成基因簇的表征 代谢物。这些研究将有助于阐明 HA 细菌如何塑造人类的机制细节 健康，并为开发可产生 GPCR 活性配体的 HA 细菌用于治疗奠定基础 控制人体生理机能。据报道，人类微生物组影响复杂的病理生理学 从免疫系统的调节到大脑和中枢发育的过程 神经系统。人类 HA 细菌数量的变化与影响 200 多种疾病有关 百万美国人，包括肥胖、糖尿病、炎症性肠病、自闭症、肠易激综合症、 和肝硬化等。源自人类 HA 细菌的疗法在以下领域具有潜在用途： 控制多种基本生物过程和人类疾病。

Project summary: The development of therapies inspired by the human microbiome is at least in part limited by our lack of understanding of how human associated (HA-) bacteria communicate with their human host. Human microbiome sequencing studies show strong correlations between changes in bacterial populations and human health. Despite these correlations and the evidence linking HA-bacteria to disease in mice, the mechanistic details of how HA-bacteria specifically affect mammalian physiology remain largely unknown. In other environments, bacteria are known to rely heavily on low molecular weight compounds (small molecules or natural products) to interact with other organisms. Similarly, we expect that HA-bacteria are likely to use small molecules to interact with their human hosts. Mounting evidence suggests that, although each human microbiome is composed of a complex collection of bacteria, a much smaller number of species is highly prevalent across the majority of individuals. While we don't know exactly which HA-bacteria are responsible for maintaining human health or causing disease, we hypothesize that small molecules produced by these commonly encountered HA-bacteria are likely to play an important role in regulating human physiology. The central aim of this proposal is to screen metabolites produced by the most commonly observed human HA- bacteria in high-throughput GPCR activity assays to identify GPCR-active small molecules and the biosynthetic gene clusters that produce them. GPCRs constitute the largest family of eukaryotic trans-membrane receptors. They are known to play diverse and profound roles in human biology and are prone to regulation by small molecules. Based on the fact that GPCRs play such an extensive role in transforming chemical information from the environment into biological signals in eukaryotic cells, I believe that HA-bacteria likely affect host physiology through the production of small molecules that interact with GPCRs. The two Aims of this proposal will result in (1) the identification, isolation, and structure elucidation of HA-bacteria-encoded metabolites that interact with diverse GPCRs and (2) the characterization of the biosynthetic gene clusters for these novel metabolites. These studies will help to illuminate the mechanistic details of how HA-bacteria shape human health and lay the groundwork for developing HA-bacteria that produce GPCR-active ligands into therapies for controlling human physiology. The human microbiome is reported to influence complex pathophysiological processes ranging from the regulation of the immune system to the development of the brain and the central nervous system. Changes in human HA-bacterial populations are associated with diseases that affect over 200 million Americans including obesity, diabetes, inflammatory bowel disease, autism, irritable bowel syndrome, and cirrhosis among many others. Therapies derived from human HA-bacteria have potential utility in controlling diverse basic biological processes and human diseases.