Cyclic Dimeric GMP, A Novel Second Messenger in Bacteria: Molecular Mechanisms

环二聚鸟苷一磷酸，c-di-GMP，在20世纪80年代被鉴定为细菌纤维素合成酶的变构激活剂，在过去的几年中已经出现作为细菌中普遍存在的第二信使。C-di-GMP影响胞外多糖合成、生物膜形成和结构、基于鞭毛和纤毛的运动性以及基因表达。这使得c-di-GMP成为从能动的单细胞生活方式转变为固着的多细胞（生物膜）生活方式的重要调节剂。此外，c-di-GMP影响细菌与动物和植物的共生和寄生相互作用。考虑到其对细菌生理学和行为的影响范围，c-di-GMP似乎至少与更知名的环核苷酸第二信使cAMP一样重要。因此，了解c-di-GMP如何运作在细菌学中具有根本的重要性。然而，除了细菌纤维素酶，c-di-GMP受体的身份，最终目标和作用机制基本上仍然未知。本项目的目的是阐明c-di-GMP运作的分子机制，使用细菌大肠杆菌作为模型。为了实现这一目标，PI的实验室将鉴定和表征该细菌中的c-di-GMP受体和最终靶标。PI还打算揭示c-di-GMP影响E.杆菌这些进展将最终导致在一个模式生物的c-di-GMP介导的信号转导的全面图片。 一般来说，社会可能会从这个项目中受益匪浅，因为这里获得的知识将提供对细菌生理学和行为的重要见解，这将允许操纵各种具有医学，农业和生物技术意义的细菌。该项目将为研究生和博士后提供跨学科的培训机会（生物信息学，细菌遗传学，蛋白质配体生物化学，生理学，转录组学和蛋白质组学）。研究经验将提供给本科生和少数民族高中学生参加夏季研究学徒计划。一个关键的微阵列实验将由PI教授的实验室课程的本科生进行，并将主要由该项目支持的高素质博士后研究员监督。这将使学生能够使用现代（和昂贵的）方法来解决现实生活中的研究问题，否则他们将无法获得。参与本项目的研究生和博士后将在PI教授的微生物生理学和代谢课程中讲授c-di-GMP。该项目的结果将在科学会议上介绍，文章将在同行评审的期刊上发表。

Cyclic dimeric guanosine monophosphate, c-di-GMP, identified in the 1980s as an allosteric activator of the bacterial cellulose synthase, has emerged in the last few years as a ubiquitous second messenger in Bacteria. C-di-GMP affects exopolysaccharide synthesis, biofilm formation and structure, flagella- and pili-based motility as well as gene expression. This makes c-di-GMP an important regulator of the transition from the motile, single-cellular lifestyle to a sessile, multicellular (biofilm) lifestyle. In addition, c-di-GMP affects symbiotic and parasitic interactions of bacteria with animals and plants. Considering the scope of its effects on bacterial physiology and behavior, c-di-GMP appears to be at least as important as the better-known cyclic nucleotide second messenger, cAMP. Therefore, understanding how c-di-GMP operates is of fundamental importance in bacteriology. However, with the exception of bacterial cellulose synthases, the identities of c-di-GMP receptors, end-targets and mechanisms of action remain essentially unknown. The objective of this project is to elucidate molecular mechanisms through which c-di-GMP operates, using bacterium Escherichia coli as a model. To achieve this objective the PI's lab will identify and characterize c-di-GMP receptors and end-targets in this bacterium. The PI also intends to uncover mechanisms by which c-di-GMP affects gene expression in E. coli. These advances will ultimately result in the comprehensive picture of c-di-GMP-mediated signal transduction in a model organism. Society in general may benefit significantly from this project because the knowledge obtained here will provide important insights into bacterial physiology and behavior, which will allow manipulation of various bacteria of medical, agricultural, and biotechnological significance. This project will provide interdisciplinary training opportunites (in bioinformatics, bacterial genetics, protein-ligand biochemistry, physiology, transcriptomics and proteomics) to the graduate student(s) and postdoctoral fellow(s) involved. Research experiences will be provided to undergraduate students and to minority high school students enrolled in the Summer Research Apprenticeship Program. A key microarray experiment will be carried out by undergraduate students enrolled in the lab course taught by the PI and will be supervised primarily by a highly qualified postdoctoral fellow supported by this project. This will allow students to address a real-life research problem using modern (and expensive) approaches, which otherwise would be inaccessible to them. The graduate student(s) and postdoctoral fellow(s) involved in this project will give lectures on c-di-GMP in the Microbial Physiology and Metabolism course taught by PI. Results of this project will be presented at scientific meetings and articles will be published in peer-reviewed journal(s).