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

项目概述：以人类微生物群为灵感的疗法的开发至少在一定程度上是有限的 这是因为我们缺乏对人类相关(HA-)细菌如何与人类宿主沟通的了解。 人类微生物组测序研究表明细菌种群的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，而且有证据表明HA细菌与小鼠的疾病有关，但 HA-细菌如何具体影响哺乳动物生理的机制细节在很大程度上仍不清楚。在……里面 在其他环境中，众所周知，细菌严重依赖低分子化合物(小分子 或天然产品)与其他生物体相互作用。同样，我们预计HA细菌可能会使用 与人类宿主相互作用的小分子。越来越多的证据表明，尽管每个人类 微生物群是由一个复杂的细菌集合组成的，数量少得多的物种是高度 在大多数人中普遍存在。虽然我们不知道是哪种HA细菌造成的 维持人类健康或导致疾病，我们假设由这些物质产生的小分子 常见的HA-细菌可能在调节人体生理方面发挥重要作用。这个 这项建议的主要目的是筛选最常见的观察到的人类HA- 细菌在高通量GPCR活性检测中鉴定具有GPCR活性的小分子及其生物合成 产生它们的基因簇。GPCRs是真核细胞跨膜受体中最大的家族。 众所周知，它们在人类生物学中扮演着不同而深远的角色，并容易受到小分子的调节 分子。基于GPCRs在转换化学信息方面发挥着如此广泛的作用 从环境到真核细胞中的生物信号，我相信HA-细菌可能会影响宿主 通过产生与GPCRs相互作用的小分子而产生的生理学。这项建议的两个目的 将导致(1)HA-细菌编码的代谢物的鉴定、分离和结构阐明 与不同的GPCR相互作用以及(2)这些新的生物合成基因簇的特征 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，并为开发产生GPCR活性配体的HA细菌用于治疗奠定基础 控制着人类的生理。据报道，人类微生物群会影响复杂的病理生理。 从免疫系统的调节到大脑和中枢神经系统的发育 神经系统。人类HA细菌种群的变化与影响200多种疾病有关 数百万美国人，包括肥胖、糖尿病、炎症性肠病、自闭症、肠易激综合征、 还有肝硬化症等。从人类HA细菌衍生的疗法在以下领域具有潜在的实用价值 控制不同的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.