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.

摘要：探索整个生命树的环状二核苷酸信号传导 所有生物都使用将外部感觉系统连接到表型的分子调节机制 输出。环状二核苷酸（CDN）第二信使分子是这样的基本系统。 从细菌到人类。在细菌中，CDN调节了许多表型，包括但不限于生物膜 形成，运动，毒力，压力反应，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。虽然CDN在整个过程中发挥了如此重要的功能 系统发育树，它们仅在细菌中进行了大约15年的深入研究，只有少数 真核系统的年。仍然有许多出色的问题，例如CDN信号的多样性 系统，诱导其生产的环境信号，感知和的分子机制 对它们的反应，表型CDN和此类信号系统的适应性益处。我的 自2008年成立以来，实验室已经研究了CDN信号，我们做出了基本贡献 到这个领域。我们的研究阐明了转录和转录后机制 CDN环状DI-GMP调节细菌病原体弧菌霍乱中的基因表达。我们也有很大的 扩展了我们对由环状DI-GMP控制的表型的理解，包括DNA修复，应力 反应和细胞曲率。我们发现并表征了环状的第一个细菌蛋白受体 GMP-AMP，一种由V.霍乱编码的磷脂酶，我们命名为CAPV。我们对新颖的CDN的搜索导致我们 发现酿酒酵母合成了循环di-ump，这是第一个检测到的嘧啶CDN 在体内，响应热冲击。我们建议通过定义循环来回答有关CDN的基本问题 DI-GMP基因调控和表型控制在V.霍乱中，并破译了这种调节网络 影响细菌健康。我们的研究还将进一步表征我们拥有的新型环状GMP-AMP途径 在霍乱葡萄球菌中发现，并将我们对环状GMP-AMP样信号通路的研究扩展到其他 细菌。最后，我们将确定酿酒酵母中的环状Di-ump合酶，确定该CDN的影响 在酵母生理学上，并在其他真核细胞中搜索环状di-ump信号传导。我们的探索 将细菌跨到真核生物将为回答有关的基本问题做出重大贡献 CDN信号传导。