Collaborative research: Information integration by gene regulatory networks controlling bacterial cell fate decisions

细菌生物膜是细胞的表面聚集体，对氯等有毒化学物质和许多用于治疗人类感染的抗生素具有高度抵抗力。该项目旨在通过分析对决策过程至关重要的基因调控网络，了解细胞如何决定形成生物膜。这些决策过程背后的机制还没有完全了解，即使是研究最深入的基因调控网络也是如此。使用生物膜形成细菌枯草芽孢杆菌作为模型，这项研究将定义通过调控网络进行决策的一般原则。枯草杆菌与许多医学上重要的病原菌密切相关并共享许多调控网络，包括梭状芽胞杆菌、蜡状芽孢杆菌和炭疽杆菌。因此，这项工作可以作为理解这些细菌如何决定启动生物膜形成的模型。该项目将为学生提供微生物学和数学建模方面的跨学科培训。将特别重视吸引休斯顿大学代表人数不足的学生，该大学已被指定为拉美裔服务机构。这项建议旨在从系统水平了解枯草杆菌细胞如何感知饥饿，并决定启动单细胞(产孢子)或多细胞(生物膜)分化计划以求生存。该提案将测试基因调控网络是否能够通过感知细胞生长速度来评估营养供应。此外，它还将研究单个主转录调控因子的不同动态(即在时间上对活性的调节)如何引导细胞转向不同的细胞命运。这些问题将通过系统和合成生物学工具的协同组合来解决，包括合成网络扰动和重新布线、单细胞成像、统计数据分析和数学建模。因此，这个项目将说明复杂(但不是太复杂)生命系统的各种基本概念。该项目还将为参与的学生和博士后提供大量的跨学科培训机会，共同从事实验和/或数学建模工作。

Bacterial biofilms, which are surface associated aggregates of cells, are highly resistant to toxic chemicals such as chlorine and to many antibiotics that are used to treat human infections. This project aims to understand how cells decide to form a biofilm by analyzing a gene regulatory network that is crucial for the decision-making process. The mechanisms underlying these decision-making processes are not fully understood, even for the best-studied gene regulatory networks. Using the biofilm-forming bacterium Bacillus subtilis as a model, this research will define general principles underlying decision making by regulatory networks. B. subtilis is closely related to and shares many regulatory networks with medically important pathogenic bacteria, including Clostridium sp., B. cereus, and B. anthracis. Hence, this work may serve as a model for understanding how such bacteria decide to initiate biofilm formation. This project will provide students with interdisciplinary training in microbiology and mathematical modeling. A special emphasis will be placed on engaging underrepresented students from the University of Houston, which has been designated as a Hispanic-Serving Institution. This proposal aims to obtain a systems-level understanding of how B. subtilis cells sense starvation and make the decision to initiate either a unicellular (sporulation) or a multicellular (biofilm) differentiation program for survival. The proposal will test whether gene-regulatory networks are able to assess nutrient availability by sensing the cell growth rate. Further, it will investigate how different dynamics (i.e. modulation of activity in time) of a single master transcriptional regulator can direct cells to alternative cell fates. These questions will be addressed with a synergistic combination of systems and synthetic biology tools, including synthetic network perturbations and rewiring, single-cell imaging, statistical data analysis, and mathematical modeling. Thus, this project will illustrate various fundamental concepts of complex (but not too complex) living systems. The project will also provide abundant interdisciplinary training opportunities for the participating students and postdocs working together on experiments and/or mathematical modeling.