EFRI-MIKS: Control of Signaling and Function by Design with Spatially Pre-Structured Microbial Communities

EFRI-MIKS：通过空间预结构化微生物群落的设计控制信号传导和功能

• 批准号: 1137089
• 负责人: Rustem Ismagilov
• 金额: $ 199.81万
• 依托单位: California Institute of Technology
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1137089&HistoricalAwards=false
• 关键词: EFRI; MIKS; Control; Signaling; Function

1137089IsmagilovThis project aims to develop a rigorous engineering framework to enhance understanding of interspeciesand interkingdom signaling in order to enable building of "microbiome in a pill" particles preciselyengineered, spatially structured microbial communities encapsulated in a biocompatible material toultimately prevent and treat human diseases associated with dysbiosis (microbial imbalance). Thisengineering framework will enable prediction and control of interspecies signaling and interactions both invitro and in vivo by solving four challenges: Goal 1 (MIKS1a): Use computational methods to predict, fora given desired function, which specific microbes are needed and which spatial structures are required toachieve that function. Goal 2 (MIKS1b and MIKS2): Develop in vitro microfluidic technologies andassociated design principles to understand signaling by rapidly characterizing and measuring the impactof spatial structure on the complex molecular interactions that underlie signaling, and host cells? responseto signaling. Goal 3 (MIKS2 and MIKS3): Develop and test design principles for the scale up of spatiallypre-structured microbial communities, discovered and characterized in Goals 1 and 2, to enableproduction of engineered functional communities in gram quantities needed for in vivo testing. Goal 4(MIKS2 and MIKS3): By using communities produced in Goal 3, and by gavaging them into germ-freeand gnotobiotic mice, measure in vivo the function of the community and the host's response, and iteratewith Goals 1-3 to develop a set of design rules that enable rational engineering of spatially pre-structured"microbiome in a pill" particles that predictably function in vivo in a mammalian gut.Intellectual Merit: The importance of multi-species and inter-kingdom systems and their signaling iswidely appreciated but general engineering approaches for control of such systems are urgently needed.This project proposes that signaling and interactions can be precisely engineered via a biomimeticapproach control of spatial structure. This is a potentially transformative shift in understanding howsignaling, metabolic exchange, and function of communities are controlled. The mammalian microbiomeis an excellent test system because it contains a diverse number of species interacting with one anotherand the host. This work will lay the foundation for a new engineering paradigm, a "microbiome in a pill",and establish design principles for controlling signaling and metabolic exchange within the community,between the community and competitors, and between the community and the host. Engineeringcommunities with spatial structure may close important gaps in understanding the mechanisms ofdysbiosis and manipulating communities affected by dysbiosis, ultimately leading to more effectiveprophylactics and treatments for human disease. The assembled team is well-qualified to carry out theproposed work: The PI has expertise in microfluidic technology development, and analysis and modelingof complex networks in biological contexts. Co-PIs Meyer and Henry are experts in automated annotationof metagenomic datasets and in using these annotations to create and analyze genome-scale metabolicmodels. Co-PIs Chervonsky and Mazmanian are experts in the use of germ-free and gnotobiotic animalmodels to understand the impact of microbiota in the mammalian gut on the host immune system.Broader Impact: Ultimately, the simple yet precisely engineered "microbiome in a pill" communitiesdesigned in this work could dramatically improve quality of life and reduce healthcare costs by modulatingdysbiosis in the context of conditions affecting millions of Americans: IBD, infections, diabetes,autoimmune conditions, and obesity. This approach may pioneer new solutions for problems wheregenetically modified microorganisms are not acceptable or feasible. The design rules for buildingfunctional microbial communities developed here should have broad impact outside of human health, withthe potential to address numerous issues facing society today, including environmental contaminants,climate, and food and fuel production, which are all strongly impacted by the function of microbialcommunities. The project will provide education, training, and mentoring for graduate and undergraduatestudents and postdoctoral scholars, enhanced by the PI's excellent track record in mentoring students.This project will also provide researchers with numerous tools to study and use microbial communities forspecific functions. Co-PIs Meyer and Henry have extensive track records in disseminating computationalmethods and tools, and the PI has an excellent track record of disseminating knowledge via high-impactpublications and partnerships with industry. This project will support public outreach through REELScience, hands-on science for K-12 curriculum development through CalTech Classroom Connection,and research training for teachers and high school students through the Summer Research Connection.

1137089 Ismagilov该项目旨在开发一个严格的工程框架，以增强对物种间和王国间信号传导的理解，以便能够构建“药丸中的微生物组”颗粒，这些颗粒被精确工程化，空间结构化的微生物群落封装在生物相容性材料中，从而彻底预防和治疗与生态失调（微生物失衡）相关的人类疾病。该工程框架将通过解决以下四个挑战来预测和控制体外和体内的种间信号传导和相互作用：目标1（MIKS 1a）：使用计算方法来预测，对于给定的期望功能，需要哪些特定的微生物以及需要哪些空间结构来实现该功能。目标2（MIKS 1b和MIKS 2）：开发体外微流控技术和相关设计原理，通过快速表征和测量空间结构对信号传导和宿主细胞基础的复杂分子相互作用的影响来理解信号传导。对信号的反应。目标3（MIKS 2和MIKS 3）：开发和测试设计原则，用于扩大目标1和2中发现和表征的空间预结构微生物群落，以实现体内测试所需的克量工程功能群落的生产。目标4（MIKS 2和MIKS 3）：通过使用目标3中产生的群落，并将其灌胃到无菌和无菌小鼠中，在体内测量群落的功能和宿主的反应，并与目标1-3迭代，以开发一套设计规则，使空间预结构的“药丸中的微生物组”颗粒能够合理工程化，这些颗粒可预测地在哺乳动物肠道中体内发挥作用。多物种和跨王国系统及其信号的重要性得到了广泛的认可，但迫切需要通用的工程方法来控制这样的系统，本项目提出，信号和相互作用可以通过仿生方法控制空间结构来精确地工程化.这是一个潜在的变革性转变，在理解如何信号，代谢交换和功能的社区是控制。哺乳动物的微生物组是一个很好的测试系统，因为它包含了多种多样的物种，这些物种彼此相互作用，并与宿主相互作用。这项工作将为一种新的工程范式奠定基础，即“药丸中的微生物组”，并建立控制社区内、社区与竞争对手之间以及社区与宿主之间的信号和代谢交换的设计原则。用空间结构设计社区可能会缩小理解生态失调机制和操纵受生态失调影响的社区的重要差距，最终导致更有效的药物和人类疾病的治疗。该团队具备开展拟议工作的资格：PI拥有微流体技术开发以及生物背景下复杂网络分析和建模的专业知识。共同研究员Meyer和亨利是宏基因组数据集自动注释方面的专家，并使用这些注释来创建和分析基因组规模的代谢模型。共同研究员Chervonsky和Mazmanian是使用无菌和无菌动物模型来了解哺乳动物肠道微生物群对宿主免疫系统影响的专家。更广泛的影响：最终，这项工作中设计的简单但精确工程化的“药丸中的微生物群”社区可以通过调节影响数百万美国人的条件下的生态失调来显著改善生活质量并降低医疗成本：IBD、感染、糖尿病、自身免疫性疾病和肥胖。这种方法可能会为转基因微生物不被接受或不可行的问题开辟新的解决方案。这里开发的构建功能性微生物群落的设计规则应该在人类健康之外产生广泛的影响，有可能解决当今社会面临的许多问题，包括环境污染物，气候，食品和燃料生产，这些都受到微生物群落功能的强烈影响。该项目将为研究生、本科生和博士后学者提供教育、培训和指导，PI在指导学生方面的出色记录也将加强这一点。该项目还将为研究人员提供许多工具，以研究和利用微生物群落的特定功能。共同PI Meyer和亨利在传播计算方法和工具方面有着广泛的记录，PI在通过高影响力的出版物和与行业的合作伙伴关系传播知识方面有着出色的记录。该项目将通过REELScience支持公众宣传，通过CalTech Classroom Connection为K-12课程开发提供实践科学，并通过Summer Research Connection为教师和高中生提供研究培训。

项目成果

Polymers in the gut compress the colonic mucus hydrogel

• DOI: 10.1073/pnas.1602789113
• 发表时间: 2016-06-28
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Datta, Sujit S.;Steinberg, Asher Preska;Ismagilov, Rustem F.
• 通讯作者: Ismagilov, Rustem F.