EFRI-MIKS: Deciphering and Controlling the Signaling Processes in Bacterial Multicellular Systems and Bacteria-Host Interactions

1137186 RenIntellectual优点：众所周知，细菌通过形成嵌入细胞外基质（称为生物膜）的表面附着的无基菌落，以及通过形成代谢不活跃的细胞（称为持久性细胞），获得对抗生素和消毒剂的内在耐受性。这种内在耐受性也通过获得性机制促进了多药耐药的发展，对微生物控制提出了巨大的挑战。尽管生物膜和持久性细胞的重要性得到了公认，但其研究仍处于起步阶段。由于生物膜结构的异质性、基因表达的时空差异以及持久性基因和生物膜基因的冗余性，持久性基因在生物膜中的分布以及环境/宿主因素和细胞-细胞信号传导对这种分布和生物膜相关的胁迫耐受性的影响尚不清楚。因此，EFRI项目的目标是通过使用整合良好的多学科方法来解决这些关键挑战，从而理解和操纵这些复杂系统中的多细胞和跨界信号过程。基于最近在表面工程，模式生物膜形成，系统生物学和分子模拟方面的成功，该研究小组将进行首次此类研究，以：(1)系统地表征生物膜发育过程中的持久性形成；(2)确定持久性形成中关键基因和信号传导过程的作用；(3)开发前所未有的计算能力，通过生物膜的细胞外基质准确预测信号因子易位；(4)合成和表征用于控制信号调节剂释放的功能纳米颗粒，以消除持久性细胞。一些重要问题将首次得到解答。这些发现将对设计更有效的基于知识的策略来操纵和控制细菌多细胞行为和细菌与宿主的相互作用产生变革性的影响。更广泛的影响：除了对生物膜发育和持久性形成的基本理解外，本研究的发现还将提高细菌生理学的一般知识，并有可能改变微生物控制的范式。此外，本研究有关病原菌和腐蚀菌的有害生物膜的研究结果可以推广到开发更好的环境友好型细菌生物膜系统，在有毒化学品的生物修复和可再生生物燃料的经济生产中具有广泛的应用前景。由于与持久性细胞和生物膜相关的广泛问题和机会，拟议的工作将对基础科学，经济，生物安全和医疗保健产生重大影响。除了取得技术成就外，该项目还将在改变大学工程教育方面发挥重要作用。与传统项目关注相对狭窄的主题不同，该项目针对多细胞和跨界信号，这是一个高度跨学科的领域。与本研究相关的高级课题将为教授现代生物技术、分子模拟、合成生物学和生物信息学提供宝贵的材料，为学生提供解决科学、工程和社会挑战的关键知识和技能。这项研究还将创造令人兴奋的拓展机会，并将有才华的年轻人，特别是代表性不足的群体，带入科学和工程事业。

1137186 RenIntellectual Merit:Bacteria are well known to obtain intrinsic tolerance to antibiotics and disinfectants by forming surfaceattachedsessile colonies embedded in an extracellular matrix, known as biofilms, and by formingmetabolically inactive cells, known as persister cells. Such intrinsic tolerance also facilitates thedevelopment of multidrug resistance through acquired mechanisms, presenting a great challenge tomicrobial control.Despite the well recognized significance, research on biofilms and persister cells is still in its infancy.Distribution of persisters in biofilms and the effects of environmental/host factors and cell-cell signalingon such distribution and biofilm-associated stress tolerance are unknown, mostly due to the heterogeneityin biofilm structure, spatial and temporal variation in gene expression, and redundancy in persister andbiofilm genes. The objective of this EFRI project is therefore to understand and manipulate themulticellular and inter-kingdom signaling processes in such complex systems by addressing these keychallenges using well integrated multidisciplinary approaches.Based on recent successes in surface engineering, patterned biofilm formation, systems biology andmolecular simulation, this research team will conduct the first-of-its-kind research to: (1) systematicallycharacterize persister formation during biofilm development, (2) identify the roles of key genes andsignaling processes in persister formation, (3) develop an unprecedented computational capability toaccurately predict signaling factor translocation through the extracellular matrix of the biofilms, and (4)synthesize and characterize functional nanoparticles for controlled release of signaling modulators toeliminate persister cells. A number of important questions will be answered for the first time. Thesediscoveries will have a transformative impact in designing more effective knowledge-based strategies forthe manipulation and control of bacterial multicellular behaviors and bacteria-host interactions.Broader Impacts:In addition to fundamental understanding of biofilm development and persister formation, the findingsfrom this study will also improve the general knowledge of bacterial physiology with the potential to shiftthe paradigm of microbial control. Furthermore, the results of this research as pertains to deleteriousbiofilms of pathogenic and corrosive bacteria can be extended to the development of better biofilmsystems of environmentally friendly bacteria, which have broad applications in bioremediation of toxicchemicals and economical production of renewable biofuels. Due to the broad spectrum of problems andopportunities associated with persister cells and biofilms, the proposed work will have significant impactson basic science, economy, biosecurity and health care.Beyond any technical achievements, this project will also play an important role in transforming collegeengineering education. Unlike traditional projects that focus on relatively narrow topics, this projecttargets multicellular and inter-kingdom signaling, a highly interdisciplinary area. The advanced topicsassociated with this research will provide invaluable materials to teach modern biotechnology, molecularsimulation, synthetic biology and bioinformatics, providing the students with crucial knowledge and skillsto address the scientific, engineering and societal challenges. This research will also create excitingoutreach opportunities and bring talented young people, especially underrepresented groups, into scienceand engineering careers.