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: 10321905
• 负责人: CHRISTOPHER M WATERS
• 金额: $ 52.54万
• 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/10321905
• 关键词: Adaptive Behaviors; Address; Bacteria; Bacterial Proteins; Bacteriophages; Cells; Cellular Morphology; Complex; Cyclic GMP; DNA Repair; Development; 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; Nucleotides; Organism; Output; Pathway interactions; Periodicity; Phenotype; Phospholipases A; Phylogenetic Analysis; Physiology; Play; Production; Pyrimidine; Regulation; Research; Saccharomyces cerevisiae; Second Messenger Systems; Signal Pathway; Signal Transduction; Signaling Molecule; System; Trees; Vibrio cholerae; Viral Cancer; Virulence; Yeasts; anti-cancer; bacterial fitness; biological adaptation to stress; cell motility; in vivo; novel; pathogenic bacteria; 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.

总结：探索生命之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 输出.环二核苷酸（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调节许多表型，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 还利用cdN进行复杂的多细胞发育途径和激活先天免疫系统 动员抗病毒和抗癌免疫反应。虽然cdn在整个网络中发挥着如此重要的作用， 在系统发育树中，它们只在细菌中被深入研究了大约15年， 在真核生物系统中。但仍有许多悬而未决的问题，如cdN信号的多样性 系统，诱导其产生的环境信号，感知和 响应于它们，表型cdNs调节，以及这种信号系统的适应性益处。我 实验室自2008年成立以来一直在研究cdN信号传导，我们做出了重要贡献 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中的基因表达。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细菌蛋白受体的环状 GMP-AMP是由霍乱弧菌编码的一种磷脂酶，我们将其命名为CapV。我们对新型cdN的研究使我们 发现酵母酿酒酵母合成环状二-UMP，检测到的第一个嘧啶cdN 在体内，对热休克的反应。我们建议通过定义循环来回答关于cdN的基本问题 霍乱弧菌中的二GMP基因调控和表型控制，并破译这种调控网络 影响细菌适应性。我们的研究还将进一步表征我们所发现的新的环GMP-AMP途径。 并将我们对环GMP-AMP样信号通路的研究扩展到其他 细菌最后，我们将确定环二UMP合酶在S。cerevisiae，确定这个cdN的影响 酵母生理学，并在其他真核细胞中寻找环状双UMP信号。我们的探险 从细菌到真核生物将对回答以下基本问题做出重大贡献： cdN信令。