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：在生命之树上探索环二核苷酸信号