Metagenetic analysis of microbial community behavior

微生物群落行为的宏遗传分析

• 批准号: 8134125
• 负责人: JO E. HANDELSMAN
• 金额: $ 48.88万
• 依托单位: YALE UNIVERSITY
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8134125
• 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）：申请应解决社会行为研究的广泛挑战区域模型生物：模型生物的识别和开发，这些生物可以综合分析社会行为的遗传，生化，生理和环境组成部分。 RFA-OD-09-00401- GM-102。最近的科学进步已经暗示了微生物群落在各种人类疾病中。这种新兴的理解表明，涉及操纵微生物群落的治疗策略。但是，当前对微生物群落行为的理解是原始的，并且不支持战略干预的设计。对微生物群落的有针对性管理将需要对个人和整个社区的社会行为的遗传，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的模型系统，可以通过遗传操纵。该系统将为微生物的社会行为的遗传，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等现象以及社区如何排除入侵者。拟议的工作将开发一个系统，以解决昆虫肠道社区曼达卡·塞克斯塔（Manduca Sexta）的知识差距。在这个项目中，我们介绍了“元植物”的概念，这是对社区表型的遗传基础的研究。我们将通过粪肠球菌确定涉及入侵社区的基因，并确定当E. faecalis是社区居民时，是否涉及相同的基因排除入侵者。我们已经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，该突变体是人类和昆虫组织的强大殖民者。这项工作的长期目标是了解微生物群落鲁棒性的性质。我们将开始使用元植物（社区行为的遗传分析）解剖这种特征。我们将使用的模型系统是Manduca Sexta（烟草虫）的肠道中的微生物群落。 Manduca是一个完善的模型系统，其中许多与人类相关的生理发现（例如心跳反转）。该系统提供了一个简单的模型，其中管理个人和社区行为的原则可以阐明。因此，我们的具体目的是：1。识别肠球菌肠球菌的突变体，这些突变体在肠道社区入侵中有缺陷。 2。在AIM1。3中鉴定出的侵袭突变体的遗传表征，表征了Manduca肠道微生物群落中入侵突变体的行为。创新：项目的创新源自概念框架，这是旧概念的新表述 - 遗传分析在社区中的应用。模型系统也是创新的，可以直接量化活动物中发光成像的微生物种群。通过此分析制定的原理最终将在更复杂的社区中进行测试，以根据经验数据制定社区中微生物行为的一般理论框架。研究人员：研究人员是霍华德·休斯医学院的一名教授，他研究了微生物生态学的遗传学已有30年了。她发表了在功能性宏基因组学（并创造单词），宿主 - 微生物相互作用，微生物相互作用和多数疾病方面的重要工作。除了她的科学专业知识外，Handelsman还是一位熟练的导师，他已经出版并提供了有关指导的国家领导。环境：。 Handelsman实验室位于威斯康星大学的细菌学系，可以使用足够的设备，空间和知识分子来有效地完成该项目。该部门最近搬到了设备齐全的现代建筑，其中包含40个微生物研究实验室，为威斯康星大学麦迪逊分校的100多个微生物学院提供了一个枢纽。影响：。这项工作有可能深刻改变微生物社区生态学领域，因为它为分析社区层面的基因型 - 表型关系提供了新的框架。模型系统可以适应其他应用程序，它可能为在面对扰动时得出有关社区行为的预测模型提供了基础。这样的模型对于为人类健康而操纵社区的最终目标至关重要。 PHS 416-1/416-9（Rev. 9/08）页面延续格式页面的工作有可能深刻改变微生物社区生态的领域，因为它为分析社区层面的基因型 - 表型关系提供了新的框架。模型系统可以适应其他应用程序，它可能为在面对扰动时得出有关社区行为的预测模型提供了基础。这样的模型对于为人类健康而操纵社区的最终目标至关重要。

项目成果

From commensal to pathogen: translocation of Enterococcus faecalis from the midgut to the hemocoel of Manduca sexta.

• DOI: 10.1128/mbio.00065-11
• 发表时间: 2011
• 期刊: mBio
• 影响因子: 6.4
• 作者: Mason KL;Stepien TA;Blum JE;Holt JF;Labbe NH;Rush JS;Raffa KF;Handelsman J
• 通讯作者: Handelsman J

Fundamentals of microbial community resistance and resilience.

• DOI: 10.3389/fmicb.2012.00417
• 发表时间: 2012
• 期刊: Frontiers in microbiology
• 影响因子: 5.2
• 作者: Shade A;Peter H;Allison SD;Baho DL;Berga M;Bürgmann H;Huber DH;Langenheder S;Lennon JT;Martiny JB;Matulich KL;Schmidt TM;Handelsman J
• 通讯作者: Handelsman J