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

细菌生物膜是表面相关的细胞聚集体，对有毒化学物质（如氯）和许多用于治疗人类感染的抗生素具有高度抗性。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来了解细胞如何决定形成生物膜。这些决策过程背后的机制尚不完全清楚，即使对研究得最好的基因调控网络也是如此。以形成生物膜的枯草芽孢杆菌为模型，本研究将定义监管网络决策的一般原则。枯草芽孢杆菌与梭状芽孢杆菌、蜡样芽孢杆菌和炭疽芽孢杆菌等医学上重要的致病菌密切相关，并共享许多调控网络。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。特别强调的是吸引来自休斯顿大学的代表性不足的学生，休斯敦大学已被指定为西班牙裔服务机构。本研究旨在获得枯草芽孢杆菌细胞如何感知饥饿并决定启动单细胞（孢子形成）或多细胞（生物膜）分化程序以生存的系统级理解。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率来评估营养可用性。此外，它将研究单个主转录调节剂的不同动力学（即活性的及时调节）如何指导细胞走向不同的细胞命运。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，这个项目将阐明复杂（但不是太复杂）生命系统的各种基本概念。项目还将为参与项目的学生和博士后提供丰富的跨学科的实验和/或数学建模培训机会。

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.