Probing the Metabolism and Cellular Roles of 2',3'-Cyclic Nucleotide Monophosphate

探讨 2,3-环核苷酸单磷酸的代谢和细胞作用

• 批准号: 9766320
• 负责人: EMILY E WEINERT
• 金额: $ 33.31万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-17 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766320
• 关键词: Address; Affect; Anti-Bacterial Agents; Apoptotic; Bacteria; Binding; Binding Proteins; Cell Death; Cell Proliferation; Cells; Cellular Stress; Cyclic AMP; Cyclic Nucleotides; Data; Engineering; Environment; Escherichia coli; Eukaryota; Future; Gene Expression; Genes; Goals; Growth; Investigation; Knowledge; Lead; Link; Mammals; Membrane; Membrane Potentials; Metabolic Pathway; Metabolism; Methods; Microbial Biofilms; Mitochondria; Molecular; Monitor; Nucleic Acids; Nucleosides; Nucleotides; Nutrient; Organ; Outcome; Pathway interactions; Phenotype; Plant Leaves; Plants; Play; Production; Prokaryotic Cells; Proteins; RNA Decay; RNA Degradation; Research; Role; Signal Pathway; Signal Transduction; Source; Stress; System; Testing; Virulence; Work; base; biological adaptation to stress; cell growth; cell motility; design; improved; in vivo; innovation; mRNA Decay; mRNA Transcript Degradation; member; novel; phosphoric diester hydrolase; repaired; response; sensor; small molecule; wound

Abstract Novel intracellular small molecules, 2’,3’-cyclic nucleotide monophosphates (2’,3’-cNMPs), have recently been discovered within both prokaryotes and eukaryotes. Within plants and mammals, wounding has been found to cause increased levels of 2’,3’-cNMPs. Preliminary studies in bacteria suggest that 2’,3’-cNMPs also are produced in response to cellular stress and that 2’,3’-cNMP levels affect bacterial phenotypes, such as biofilm formation and motility, and expression of numerous genes. The long-term goal of this research is to understand the roles of 2’,3’-cNMPs in controlling prokaryotic signaling pathways and to utilize this knowledge to design small molecules to modulate cellular phenotypes. This goal will be addressed by investigating the cellular components involved in 2’,3’-cNMP metabolism, identifying 2’,3’-cNMP sensors, and determining the effects of 2’,3’-cNMPs on downstream pathways in a wide range of bacteria. The proposed work outlines an innovative research plan to probe a novel cellular stress-sensing mechanism and will provide molecular level details about the nucleic acids and proteins involved in 2’,3’-cNMP metabolism, as well as the downstream cellular phenotypes. The proposed studies also will expand knowledge of cellular mRNA decay pathways within bacteria because 2’,3’-cNMPs are products of mRNA degradation. This work is anticipated to yield the following expected outcomes. First, it will identify the proteins responsible for 2’,3’-cNMP production and degradation in vivo, as well as 2’,3’-cNMP binding proteins that may control downstream phenotypes. These studies also will highlight the distribution of 2’,3’-cNMPs within the bacterial kingdom and extend our understanding of mRNA decay within prokaryotes. Second, the proposed work will identify the effects of altering 2’,3’-cNMP levels in an array of bacteria, including changes in gene expression, phenotypes, and key metabolic pathways, including nucleotide/nucleoside metabolism. Third, elucidating conditions that alter 2’,3’-cNMP levels and phenotypes controlled by 2’,3’-cNMPs will highlight their role in bacterial responses to cellular stress, particularly with regards to cellular proliferation and biofilm formation, and illuminate additional effects of stress on mRNA decay. The proposed work will have an important positive impact by dissecting the cellular roles of 2’,3’-cNMPs within bacteria, which will highlight novel pathways within prokaryotes and, in the future, potentially can be engineered to control bacterial proliferation.

抽象的 新型细胞内小分子，2'，3'-cycle核单磷酸盐（2'，3'-CNMP）最近具有 我们在原核生物和真核生物中都被发现。在植物和哺乳动物中，获胜 发现导致2'，3'-CNMP的水平增加。细菌的初步研究表明2'，3'-CNMP 还会响应细胞应激而产生2'，3'-CNMP水平影响细菌表型，例如 作为生物膜的形成和运动，以及许多基因的表达。这项研究的长期目标是 了解2'，3'-CNMP在控制原核信号通路中的作用并利用这一点 知识设计小分子以调节细胞表型。这个目标将由 研究涉及2'，3'-CNMP代谢的细胞成分，识别2'，3'-CNMP传感器， 并确定2'，3'-CNMP对多种细菌中下游途径的影响。 拟议的工作概述了一项创新的研究计划，以探究新型的细胞应激感应机制和 将提供有关涉及2'，3'-CNMP代谢的核酸和蛋白质的分子水平细节， 以及下游的细胞表型。拟议的研究还将扩大有关的知识 细胞mRNA衰变途径在细菌中，因为2'CNMP是mRNA降解的产物。 预计这项工作将产生以下预期的结果。首先，它将识别蛋白质 负责体内2'，3'-CNMP产生和降解，以及2'，3'-CNMP结合蛋白 可能控制下游表型。这些研究还将突出显示2'，3'-CNMP的分布 细菌王国并扩展了我们对原核生物中mRNA衰变的理解。第二， 拟议的工作将确定在一系列细菌中改变2'，3'-CNMP水平的影响，包括变化 在基因表达，表型和关键代谢途径中，包括核苷酸/核苷代谢。 第三，阐明2'，3'-CNMP水平和由2'，3'-CNMP控制的表型会改变的条件 突出显示它们在细菌对细胞应激的反应中的作用，特别是在细胞增殖方面 和生物膜的形成，并照亮了压力对mRNA衰变的其他影响。拟议的工作将 通过在细菌中剖析2'，3'-CNMP的细胞作用，从而产生重要的积极影响，这将会 突出探针内的新颖途径，将来可以设计用于控制 细菌增殖。