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

环二聚鸟苷单磷酸，c-二- gmp，在20世纪80年代被确定为细菌纤维素合成酶的变构激活剂，近年来作为细菌中普遍存在的第二信使出现。c -二gmp影响胞外多糖的合成、生物膜的形成和结构、鞭毛和毛的运动以及基因表达。这使得c-di-GMP成为从运动的单细胞生活方式向固定的多细胞（生物膜）生活方式转变的重要调节剂。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-二gmp如何运作在细菌学中具有重要的基础意义。然而，除细菌纤维素合酶外，c-二gmp受体的特性、最终靶点和作用机制基本上仍然未知。本项目旨在以大肠杆菌为模型，阐明c-di-GMP的分子机制。为了实现这一目标，PI的实验室将在这种细菌中识别和表征c-二gmp受体和最终靶点。PI还打算揭示c-di-GMP影响大肠杆菌基因表达的机制。这些进展将最终导致c-di- gmp在模式生物中介导的信号转导的全面图景。整个社会可能会从这个项目中显著受益，因为在这里获得的知识将提供对细菌生理和行为的重要见解，这将允许操纵各种具有医学、农业和生物技术意义的细菌。该项目将为参与的研究生和博士后提供跨学科培训机会（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报名参加暑期研究学徒计划。一个关键的微阵列实验将由参加PI讲授的实验课的本科生进行，并将主要由本项目支持的高素质博士后进行指导。这将允许学生使用现代（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这些方法。本课题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。该项目的研究结果将在科学会议上发表，文章将发表在同行评议的期刊上。

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).