Metagenetic analysis of microbial community behavior

微生物群落行为的宏遗传分析

• 批准号: 7821725
• 负责人: JO E. HANDELSMAN
• 金额: $ 47.51万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7821725
• 关键词: Address; Animal Model; Animals; Area; Bacteriology; Behavior; Biochemical; Biological Models; Characteristics; Coin; Communities; Complex; Data; Development; Disease; Drug Formulations; Ecology; Enterococcus faecalis; Environment; Equipment; Exclusion; Face; Faculty; Foundations; Genes; Genetic; Genotype; Goals; Health; Human; Image; Imaging Techniques; Individual; Insecta; Institutes; Intervention; Knowledge; Leadership; Life; Manduca; Manduca sexta; Medical; Mentors; Metagenomics; Microbe; Microbial Genetics; Microbiology; Modeling; Names; Nature; Phenotype; Physiological; Population; Publishing; Research; Research Personnel; Scientific Advances and Accomplishments; Social Behavior; System; Testing; Tissues; Universities; Wisconsin; Work; base; design; genetic analysis; human disease; innovation; luminescence; microbial; microbial community; microorganism; microorganism interaction; mutant; optical imaging; predictive modeling; professor; treatment strategy

DESCRIPTION (provided by applicant): The application addresses broad challenge area Model organisms for social behavior studies: Identification and development of model organisms that allow for integrative analyses of the genetic, biochemical, physiological, and environmental components of social behavior. RFA-OD-09-00401- GM-102. Recent scientific advances have implicated microbial communities in a broad range of human diseases. This emerging understanding suggests treatment strategies that involve manipulating microbial communities. However, current understanding of the behavior of microbial communities is primitive and does not support the design of strategic interventions. Targeted management of microbial communities will require an integrated understanding of the genetic, biochemical, physiological, and environmental components of social behavior of individuals and of the community as a whole. Such an understanding, in turn, requires a model system that is simple and can be manipulated genetically. This system will provide the foundation for integrative analyses of the genetic, biochemical, physiological, and environmental components of social behavior of microorganisms, including phenomena such as invasion of microbial communities and how communities exclude invaders. The proposed work will develop a system for addressing this knowledge gap in the gut community of the insect, Manduca sexta. In this project, we introduce the concept of "metagenetics," which is the study of the genetic basis for community phenotypes. We will identify genes involved in invasion of the community by Enterococcus faecalis, and determine whether the same genes are involved in exclusion of invaders when E. faecalis is a community resident. We have developed an optical imaging technique to screen luminescent mutants of E. faecalis strain OGR1F, which is a powerful colonist of both human and insect tissue. The long-term goal of this work is to understand the nature of robustness of microbial communities. We will begin to dissect this characteristic using metagenetics, the genetic analysis of community behavior. The model system we will use is the microbial community in the gut of Manduca sexta, the tobacco hornworm. Manduca is a well-established model system in which many physiological discoveries relevant to humans have been made (such as heartbeat reversal). The system provides a simple model in which the principles governing individual and community behavior can be elucidated. As such, our specific aims are to: 1. Identify mutants of Enterococcus faecalis that are defective in gut community invasion. 2. Genetically characterize invasion mutants identified in Aim 1. 3. Characterize behavior of invasion mutants in the Manduca gut microbial community. Innovation: The project's innovation derives from the conceptual framework, which is a new formulation of an old concept - application of genetic analysis to communities. The model system is also innovative, enabling direct quantification of microbial populations with luminescence imaging in live animals. The principles developed through this analysis will be tested ultimately in more complex communities to formulate a general theoretical framework for microbial behavior in communities based on empirical data. Investigator: The investigator is a Howard Hughes Medical Institute Professor who has studied the genetics of microbial ecology for 30 years. She has published significant work in functional metagenomics (and coined the word), host-microbe interactions, microbial interactions, and polymicrobial disease. In addition to her scientific expertise, Handelsman is a skilled mentor who has published and provided national leadership on mentoring. Environment:. Situated in the Department of Bacteriology at the University of Wisconsin, the Handelsman lab has access to sufficient equipment, space, and intellectualism to complete this project effectively. The department recently moved to a well-equipped, modern building that contains 40 microbiology research labs, providing a hub for the more than 100 microbiology faculty at the University of Wisconsin-Madison. Impact:. The work has the potential to profoundly alter the field of microbial community ecology because it provides a new framework for analysis of genotype-phenotype relationships at the community level. The model system may be adapted to other applications and it may provide the basis for deriving predictive models about community behavior in the face of perturbation. Such models are essential to the ultimate goal of manipulating communities for the benefit of human health. PHS 416-1/416-9 (Rev. 9/08) Page Continuation Format Page The work has the potential to profoundly alter the field of microbial community ecology because it provides a new framework for analysis of genotype-phenotype relationships at the community level. The model system may be adapted to other applications and it may provide the basis for deriving predictive models about community behavior in the face of perturbation. Such models are essential to the ultimate goal of manipulating communities for the benefit of human health.

描述（由申请人提供）：该申请解决了广泛的挑战领域用于社会行为研究的模式生物：识别和开发允许对社会行为的遗传、生化、生理和环境组成部分进行综合分析的模式生物。 RFA-OD-09-00401-GM-102。最近的科学进展表明微生物群落与多种人类疾病有关。这种新的认识提出了涉及操纵微生物群落的治疗策略。然而，目前对微生物群落行为的理解还很原始，不支持战略干预措施的设计。对微生物群落的有针对性的管理需要对个体和整个群落的社会行为的遗传、生化、生理和环境组成部分进行综合理解。反过来，这种理解需要一个简单且可以遗传操作的模型系统。该系统将为微生物社会行为的遗传、生化、生理和环境组成部分的综合分析提供基础，包括微生物群落的入侵以及群落如何排斥入侵者等现象。拟议的工作将开发一个系统来解决昆虫天蛾肠道群落中的这一知识差距。在这个项目中，我们引入了“宏遗传学”的概念，即群落表型遗传基础的研究。我们将鉴定与粪肠球菌入侵群落有关的基因，并确定当粪肠球菌为社区居民时，相同的基因是否参与排除入侵者。我们开发了一种光学成像技术来筛选粪肠球菌菌株 OGR1F 的发光突变体，该菌株是人类和昆虫组织的强大定殖者。这项工作的长期目标是了解微生物群落稳健性的本质。我们将开始使用元遗传学（即群体行为的遗传分析）来剖析这一特征。我们将使用的模型系统是烟草天蛾（Manduca sexta）肠道中的微生物群落。 Manduca 是一个完善的模型系统，其中已经做出了许多与人类相关的生理学发现（例如心跳逆转）。该系统提供了一个简单的模型，可以在其中阐明控制个人和社区行为的原则。因此，我们的具体目标是： 1. 鉴定在肠道群落入侵方面存在缺陷的粪肠球菌突变体。 2. 对目标 1 中确定的入侵突变体进行遗传学表征。 3. 对曼杜卡肠道微生物群落中入侵突变体的行为进行表征。创新：该项目的创新源于概念框架，这是一个旧概念的新表述——遗传分析在社区中的应用。该模型系统也是创新的，可以通过活体动物的发光成像直接量化微生物种群。通过这种分析得出的原理最终将在更复杂的群落中进行测试，以根据经验数据制定群落中微生物行为的通用理论框架。调查员：调查员是霍华德休斯医学研究所教授，研究微生物生态遗传学30年。她在功能宏基因组学（并创造了这个词）、宿主-微生物相互作用、微生物相互作用和多微生物疾病方面发表了重要的工作。除了她的科学专业知识之外，汉德尔斯曼还是一位技术精湛的导师，她发表过文章并在指导方面发挥了国家领导作用。环境：。 Handelsman 实验室位于威斯康星大学细菌学系，拥有足够的设备、空间和智力来有效地完成该项目。该系最近搬到了一座设备齐全的现代化建筑，其中包含 40 个微生物学研究实验室，为威斯康星大学麦迪逊分校 100 多名微生物学教师提供了中心。影响：。这项工作有可能深刻改变微生物群落生态学领域，因为它为分析群落水平的基因型-表型关系提供了新的框架。该模型系统可以适应其他应用，并且可以为推导有关面对扰动时的社区行为的预测模型提供基础。这些模型对于操纵社区以造福人类健康的最终目标至关重要。 PHS 416-1/416-9（修订版 9/08）页面延续格式页面 这项工作有可能深刻改变微生物群落生态学领域，因为它为群落水平的基因型-表型关系分析提供了新的框架。该模型系统可以适应其他应用，并且可以为推导有关面对扰动时的社区行为的预测模型提供基础。这些模型对于操纵社区以造福人类健康的最终目标至关重要。