Probing the role of sensory cues in the regulation of bacterial biofilm development

探讨感觉线索在细菌生物膜发育调节中的作用

• 批准号: 10714322
• 负责人: Sampriti Mukherjee
• 金额: $ 40.13万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714322
• 关键词: 3-Dimensional; Architecture; Bacteria; Basic Science; Behavior; Biochemistry; Biological; Biological Models; Chemicals; Communities; Cues; Decision Making; Development; Environment; Fluorescence Microscopy; Goals; Individual; Knowledge; Learning; Life Style; Light; Mediating; Microbial Biofilms; Molecular; Molecular Biology; Multi-Drug Resistance; Nutrient; Nutrient availability; Organism; Pathway interactions; Photoreceptors; Population Density; Process; Pseudomonas aeruginosa; Regulation; Repression; Research; Role; Sensory; Signal Pathway; Signal Transduction; Stimulus; Structure; System; Virulence; Work; antimicrobial tolerance; bacterial genetics; clinically relevant; design; detection of nutrient; genome-wide; human pathogen; interdisciplinary approach; mathematical model; multidrug-resistant Pseudomonas aeruginosa; multiple drug use; novel therapeutic intervention; pathogen; programs; quorum sensing; response; sensory input; sensory integration; structural biology

PROJECT SUMMARY Bacteria have a remarkable ability to sense diverse stimuli and make regulatory decisions to elicit an appropriate response. The objective of our research program is to understand the molecular underpinnings of this cellular decision-making process during the development of three dimensional (3D) structured communities called biofilms. Biofilms represent a predominant bacterial lifestyle and are crucial for antimicrobial tolerance, virulence, and environmental persistence in diverse pathogens including multi-drug resistant Pseudomonas aeruginosa. P. aeruginosa serves as an ideal clinically relevant model system for our basic research in biofilms because it adapts to and forms biofilms in a wide variety of environments, and the biofilm matrix components in this organism are well characterized. The overarching goal of the proposed research is to define how bacteria decode and integrate sensory cues – physical, chemical and biological – over the course of the biofilm development cycle. My work has shown that light (physical cue) detected via bacteriophytochrome BphP photoreceptor mediated photo sensing and population density (biological cue) detected via RhlR mediated quorum sensing represses biofilms. Furthermore, we have discovered that nutrient availability (chemical cue) converges with quorum sensing (biological cue) to control biofilm matrix components and architecture. Over the next five years, we will build on our recent discoveries and use a multidisciplinary approach combining bacterial genetics, molecular biology, biochemistry, fluorescence microscopy, mathematical modeling, structural biology and genome-scale studies to define sensory signaling in the context of a growing biofilm. First, we will investigate how light is perceived locally and globally in heterogenous biofilms and characterize the BphP photo-sensing signaling system to understand the regulation of photo sensing in P. aeruginosa (Project 1). Second, we will dissect the CbrA-Crc nutrient-sensing pathway to learn how nutrient availability controls biofilm development (Project 2). Third, we will delineate the different ways by which RhlR mediated quorum sensing represses biofilm formation (Project 3). Finally, we will define how information from two or more distinct sensory signaling pathways are combined in the control of collective behaviors (Project 4). Our research will establish a broadly relevant framework for understanding how information encoded in diverse sensory inputs is extracted and integrated to drive collective behaviors – knowledge that is crucial for designing successful synthetic strategies to enhance or to inhibit biofilms and for developing novel therapeutic interventions.

项目概要 细菌具有非凡的能力来感知不同的刺激并做出调节决定以引发适当的反应。 我们研究计划的目标是了解这种细胞的分子基础。 三维 (3D) 结构化社区开发过程中的决策过程称为 生物膜代表了主要的细菌生活方式，对于抗菌素耐受性、毒力、 以及多种病原体（包括多重耐药铜绿假单胞菌）的环境持久性。 铜绿假单胞菌作为我们生物膜基础研究的理想相关模型系统，因为它 适应并在多种环境中形成生物膜，其中的生物膜基质成分 拟议研究的首要目标是确定细菌如何解码。 并在生物膜形成过程中整合物理、化学和生物的感官线索 我的工作表明，光（物理线索）是通过细菌光敏色素 BphP 光感受器检测到的。 通过 RhlR 介导的群体感应检测介导的光感应和人口密度（生物线索） 此外，我们发现营养可用性（化学线索）与生物膜一致。 群体感应（生物线索）来控制生物膜基质成分和结构在未来五年内， 我们将基于我们最近的发现，并使用结合细菌遗传学的多学科方法， 分子生物学、生物化学、荧光显微镜、数学建模、结构生物学和 在不断生长的生物膜背景下进行基因组规模的研究来定义感觉信号传导首先，我们将进行研究。 如何在异质生物膜中局部和全局感知光并表征 BphP 光传感 了解铜绿假单胞菌光传感调节的信号系统（项目 1）。 剖析 CbrA-Crc 营养感应途径，了解营养可用性如何控制生物膜的形成 （项目 2）第三，我们将描述 RhlR 介导的群体感应抑制生物膜的不同方式。 最后，我们将定义来自两个或多个不同感觉信号通路的信息。 结合在集体行为的控制中（项目 4）。 用于理解如何提取和整合不同感官输入中编码的信息的框架 推动集体行为——对于设计成功的综合策略以增强或增强作用至关重要的知识 抑制生物膜并开发新的治疗干预措施。