Identifying and characterizing small molecules from the human microbiome

描述(由申请人提供) 摘要：人类微生物群计划(HMP)正在产生大量有关人类相关微生物群落组成和动态的数据，最近的其他研究表明，微生物群落组成的变化与人类疾病相关。这一提议源于我的实验室最近出人意料地发现，与人类相关的细菌产生类似药物的小分子，它将使用HMP数据作为起点，从与人类相关的微生物中识别和表征新的小分子。这个项目有三个共同的动机：第一，HMP是美国国立卫生研究院的路线图倡议，正在生成关于与人类相关的微生物群落的组成和动态的丰富数据。微生物组的组成和人类疾病之间的新联系正在被越来越频繁地发现，但需要进行功能研究来将这些数据转化为新的治疗方法。该项目将建立这样一座桥梁，使用HMP数据来支持对人类相关细菌的功能研究，这可能导致新的益生菌疗法。其次，来自人类相关细菌的小分子可能具有重要的活动。鉴于微生物产生的小分子调节物种间相互作用的强大先例，来自人类微生物组的小分子可能调节微生物组内和宿主-微生物组之间的相互作用，这两者都将对人类健康产生重要影响。该项目将使用HMP数据来识别和表征人类微生物群中调节物种间相互作用的新的小分子。第三，工程益生菌在未来可能会很常见，并将是人类微生物组项目对人类健康最直接的好处之一。与人类基因组不同的是，人类微生物群是我们可以控制其组成的“超基因组”的组成部分。该项目将为设计新的益生菌菌株奠定基础，为HMP与临床的直接联系创造了可能性。 公共卫生相关性：天然产品--来自微生物的小分子--一直是临床使用的抗生素、抗真菌药物、抗癌剂、免疫抑制剂和其他药物的主要来源。这项提案描述了从一种不同寻常的来源--与人类相关的微生物--发现和表征自然产品的新方法。识别和表征这些分子不仅将有助于更好地了解人类微生物群和人类疾病之间的联系，还将为设计新的益生菌菌株(如酸奶中发现的细菌)奠定基础，这些细菌可以促进人类健康，帮助抗击克罗恩病和肥胖症等疾病。

DESCRIPTION (Provided by the applicant) Abstract: The Human Microbiome Project (HMP) is generating a wealth of data about the composition and dynamics of human-associated microbial communities, and other recent efforts have shown that changes in the composition of the microbiome are correlated with human diseases. This proposal, which originated with my laboratory's recent and unexpected finding that human-associated bacteria produce drug-like small molecules, will use HMP data as a starting point for identifying and characterizing new small molecules from human-associated microbes. There are three convergent motivations for this project: First, the HMP, an NIH Roadmap Initiative, is generating a wealth of data about the composition and dynamics of human-associated microbial communities. New connections between the composition of the microbiome and human disease are being discovered with increasing frequency, but functional studies are needed to translate this data into new therapies. This project will build one such bridge, using HMP data to support functional studies on human-associated bacteria that could lead to new probiotic therapies. Second, small molecules from human-associated bacteria are likely to have important activities. Given the strong precedent for microbially-produced small molecules to mediate interspecies interactions, small molecules from the human microbiome are likely to mediate intra-microbiome and host- microbiome interactions, both of which will have an important bearing on human health. This project will use HMP data to identify and characterize new small molecules from the human microbiome that mediate interspecies interactions. Third, engineered probiotics are likely to be common in the future, and will be one of the most direct benefits to human health from the Human Microbiome Project. Unlike the human genome, the human microbiome is a component of our 'supra-genome' whose composition we can control. This project will lay the groundwork for engineering new probiotic bacterial strains, creating the potential for a direct link from the HMP to the clinic. Public Health Relevance: Natural products - small molecules from microbes - have been a primary source of clinically-used antibiotics, antifungals, anticancer agents, immunosuppressants, and other drugs. This proposal describes new approaches to discovering and characterizing natural products from an unusual source: human-associated microbes. Identifying and characterizing these molecules will not only lead to a greater understanding of the connection between the human microbiome and human disease, it will also lay the groundwork for engineering new probiotic bacterial strains (like the bacteria found in yogurt) that could promote human health and help fight diseases like Crohn's disease and obesity.