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

环状二聚体 GMP，细菌中的新型第二信使：分子机制

• 批准号: 1052575
• 负责人: Mark Gomelsky
• 金额: $ 73.23万
• 依托单位: University of Wyoming
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1052575&HistoricalAwards=false
• 关键词: Cyclic; Dimeric; GMP; Novel; Second

Cyclic dimeric guanosine monophosphate, c-di-GMP, is a key molecule involved in the lifestyle switch in bacteria, from single motile cells to surface-attached multicellular communities (biofilms). c-di-GMP controls this lifestyle switch by affecting bacterial motility, adhesion to surfaces, synthesis of extracellular matrix, stress resistance, and virulence. Gaining mechanistic insights into how c-di-GMP functions is of fundamental importance in bacteriology. Currently, a glaring gap exists between the large numbers of enzymes involved in c-di-GMP synthesis and hydrolysis (several dozen in most proteobacteria) and the small numbers (low single digits) of known c-di-GMP receptors, or effector proteins. This gap indicates that many c-di-GMP receptors have escaped identification. The long-term objective of this project is to identify new c-di-GMP receptors and uncover molecular mechanisms through which they operate in a model bacterium, Escherichia coli. In this project, new c-di-GMP receptors will be identified by genetic means as well as by the affinity-based capture. Because c-di-GMP, like other second messengers, works though conserved molecular mechanisms, it is expected that the insights derived from E. coli will inform strategies on controlling behavior of various bacterial species of medical, agricultural, environmental and biotechnological significance. The broader merit of this proposal lies in understanding the mechanisms that control bacterial behavior. This understanding is critical for designing pharmacological interventions that would allow us to manipulate bacteria in desirable ways. This project will offer interdisciplinary training opportunities in bioinformatics, bacterial genetics, protein-ligand biochemistry, and physiology to graduate and undergraduate students who will comprise the core research personnel. It will also provide research experiences to minority high school students enrolled in the Summer Research Apprenticeship Program. The project results will be presented at scientific meetings and published in research papers as well as in the articles for broader audiences.

环二聚鸟苷单磷酸，c-di-GMP，是参与细菌生活方式转换的关键分子，从单个运动细胞到表面附着的多细胞群落（生物膜）。c-di-GMP通过影响细菌的运动、表面粘附、细胞外基质的合成、抗逆性和毒力来控制这种生活方式的转换。获得对c-二gmp如何发挥作用的机制见解在细菌学中是至关重要的。目前，在大量参与c-di-GMP合成和水解的酶（大多数变形菌中有几十种）和少量已知的c-di-GMP受体或效应蛋白（低个位数）之间存在着明显的差距。这一差距表明许多c-二gmp受体没有被识别。该项目的长期目标是鉴定新的c-di-GMP受体，并揭示它们在模型细菌大肠杆菌中运作的分子机制。在这个项目中，新的c-di-GMP受体将通过遗传方法和基于亲和力的捕获来鉴定。因为c-di-GMP，像其他第二信使一样，通过保守的分子机制起作用，预计从大肠杆菌中获得的见解将为控制医学，农业，环境和生物技术意义上的各种细菌物种的行为提供策略。这一建议的更广泛的优点在于理解控制细菌行为的机制。这种理解对于设计药物干预是至关重要的，这将使我们能够以理想的方式操纵细菌。该项目将为研究生和本科生提供生物信息学、细菌遗传学、蛋白质配体生物化学和生理学等跨学科的培训机会，他们将成为核心研究人员。它还将为参加暑期研究学徒计划的少数民族高中生提供研究经验。该项目的结果将在科学会议上提出，并在研究论文以及面向更广泛读者的文章中发表。