Exploring cyclic di-nucleotide signaling across the tree of life

探索生命树中的环状二核苷酸信号传导

• 批准号: 10547744
• 负责人: CHRISTOPHER M WATERS
• 金额: $ 52.46万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10547744
• 关键词: Adaptive Behaviors; Bacteria; Bacterial Proteins; Bacteriophages; Cells; Cellular Morphology; Complex; Cyclic GMP; DNA Repair; Dinucleoside Phosphates; Environment; Eukaryota; Eukaryotic Cell; Gene Expression; Gene Expression Regulation; Genetic Transcription; Heat-Shock Response; Human; Immune response; Innate Immune System; Laboratories; Life; Microbial Biofilms; Molecular; Names; Organism; Output; Pathway interactions; Periodicity; Phenotype; Phospholipases A; Phylogenetic Analysis; Physiology; Play; Production; Pyrimidine; Regulation; Research; Saccharomyces cerevisiae; Second Messenger Systems; Signal Induction; Signal Pathway; Signal Transduction; Signaling Molecule; System; Trees; Vibrio cholerae; Viral Cancer; Virulence; Yeasts; anti-cancer; bacterial fitness; biological adaptation to stress; cell motility; cellular development; in vivo; novel; pathogenic bacteria; posttranscriptional; receptor; response; sensory system

Summary: Exploring cyclic di-nucleotide signaling across the tree of life All organisms utilize molecular regulatory mechanisms connecting external sensory systems to phenotypic output. Cyclic di-nucleotide (cdN) second messenger molecules are one such fundamental system conserved from bacteria to humans. In bacteria, cdNs regulate numerous phenotypes including but not limited to biofilm formation, motility, virulence, stress responses, DNA repair, cell morphology, and phage defense. Eukaryotes also utilize cdNs for complex multicellular development pathways and activation of the innate immune system to mobilize anti-viral and anti-cancer immune responses. Although cdNs play such important functions across the phylogenetic tree, they have only been intensively studied for about 15 years in bacteria and only a few years in eukaryotic systems. There remain many outstanding questions such as the diversity of cdN signaling systems, the environmental signals that induce their production, the molecular mechanisms that sense and respond to them, the phenotypes cdNs regulate, and the adaptive benefit of such signaling systems. My laboratory has studied cdN signaling since its inception in 2008, and we have made fundamental contributions to this field. Our research has elucidated both transcriptional and post-transcriptional mechanisms by which the cdN cyclic di-GMP regulates gene expression in the bacterial pathogen Vibrio cholerae. We have also greatly expanded our understanding of the phenotypes controlled by cyclic di-GMP including DNA repair, stress responses, and cell curvature. We discovered and characterized the first bacterial protein receptor of cyclic GMP-AMP, a phospholipase encoded by V. cholerae we named CapV. Our search for novel cdNs led us to discover that the yeast Saccharomyces cerevisiae synthesizes cyclic di-UMP, the first pyrimidine cdN detected in vivo, in response to heat shock. We propose to answer fundamental questions about cdNs by defining cyclic di-GMP gene regulation and phenotypic control in V. cholerae and deciphering how such regulatory networks impact bacterial fitness. Our studies will also further characterize the novel cyclic GMP-AMP pathway we have discovered in V. cholerae and extend our studies of cyclic GMP-AMP-like signaling pathways into other bacteria. Finally, we will identify the cyclic di-UMP synthase in S. cerevisiae, determine the impact of this cdN on yeast physiology, and search for cyclic di-UMP signaling in other eukaryotic cells. Our explorations spanning bacteria to eukaryotes will make significant contributions to answering fundamental questions about cdN signaling.

摘要：探索生命树中的环状二核苷酸信号传导 所有生物体都利用分子调节机制将外部感觉系统与表型连接起来 输出。环状二核苷酸（cdN）第二信使分子就是这样一种保守的基本系统 从细菌到人类。在细菌中，CDN 调节多种表型，包括但不限于生物膜 形成、运动性、毒力、应激反应、DNA 修复、细胞形态和噬菌体防御。真核生物 还利用 cdN 进行复杂的多细胞发育途径和先天免疫系统的激活 动员抗病毒和抗癌免疫反应。尽管 cdN 在各个领域都发挥着如此重要的作用 就系统发育树而言，它们在细菌中的深入研究仅持续了大约 15 年，而且只有少数 在真核系统中工作多年。仍然存在许多悬而未决的问题，例如 cdN 信号的多样性 系统、诱导其产生的环境信号、感知和 对它们的反应、cdN 调节的表型以及此类信号系统的适应性益处。我的 实验室自2008年成立以来一直在研究cdN信令，并做出了基础性贡献 到这个领域。我们的研究阐明了转录和转录后机制 cdN 环状二-GMP 调节细菌病原体霍乱弧菌的基因表达。我们也大大 扩大了我们对环二 GMP 控制的表型的理解，包括 DNA 修复、应激 反应和细胞曲率。我们发现并鉴定了第一个环状细菌蛋白受体 GMP-AMP，一种由霍乱弧菌编码的磷脂酶，我们将其命名为 CapV。我们对新颖的 CDN 的搜索使我们发现 发现酿酒酵母合成环二-UMP，这是第一个检测到的嘧啶 cdN 在体内，对热休克的反应。我们建议通过定义循环来回答有关 cdN 的基本问题 霍乱弧菌中的 di-GMP 基因调控和表型控制以及破译此类调控网络的机制 影响细菌的适应性。我们的研究还将进一步表征我们拥有的新型环 GMP-AMP 途径 在霍乱弧菌中发现，并将我们对环 GMP-AMP 样信号通路的研究扩展到其他领域 细菌。最后，我们将鉴定酿酒酵母中的环状二-UMP合酶，确定该cdN的影响 研究酵母生理学，并在其他真核细胞中寻找环状双 UMP 信号传导。我们的探索 从细菌到真核生物，将为回答以下基本问题做出重大贡献： cdN 信号传导。