Discovery and characterization of new toxins in genomes and metagenomes of bloom-forming cyanobacteria

水华形成蓝藻基因组和宏基因组中新毒素的发现和表征

• 批准号: 10427316
• 负责人: Gregory James Dick
• 金额: $ 2.06万
• 依托单位: BOWLING GREEN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427316
• 关键词: Address; Algal Blooms; Anabolism; Biochemical; Biochemistry; Bioinformatics; Biological; Characteristics; Chemicals; Collaborations; Communities; Complex; Cyanobacterium; DNA sequencing; Data; Databases; Development; Environmental Health; Enzymes; Gene Cluster; Gene Expression; Genes; Genetic; Genome; Genomics; Goals; Graph; Health; Human; Information Dissemination; Infrastructure; Investigation; Laboratories; Link; Manuals; Metagenomics; Methods; Microcystis; Mining; Natural Products; Nature; Organism; Outcome; Pathway interactions; Population; Production; Receptor Signaling; Regulation; Research Priority; Research Project Grants; Resources; Sampling; Severities; Signal Transduction Pathway; Source; Structure; Technology; Testing; Toxin; base; bioactive natural products; bioinformatics pipeline; climate change; data streams; diverse data; harmful algal blooms; high throughput screening; human disease; metabolomics; metagenome; microorganism; next generation; novel; water quality

Abstract: Discovery and characterization of new toxins Microcystis and other cyanobacteria commonly found in cyanobacterial harmful algal blooms (cHABs) harbor numerous gene clusters that encode the biosynthesis of diverse and unknown natural products. This project will test the hypothesis that these gene clusters are responsible for production of variety of unknown toxins and bioactive compounds that threaten human and environmental health yet remain invisible to current methods commonly used to assess water quality. The goal is to identify novel toxins and their specific genetic pathways for biosynthesis and regulation through the study of both pure cultures and consortia of uncultured microorganisms. Genomes will be assembled from metagenomes and from representative cultures of dominant bloom-forming cyanobacterial species. High-throughput bioinformatic mining of genomes and metagenomes will identify and prioritize targets for manual curation and structure prediction. In parallel to these gene-based studies, analysis of cultures and field samples will be analyzed via (i) high-throughput screening for a variety of bioactivities at the U-M Center for Chemical Genomics, and (ii) metabolomics studies (conducted by Wilhelm and Boyer groups), and (iii) assessment of potential biological targets relating to human disease. Taken together, results on the genetic/biochemical novelty and abundance and expression of genes in Lake Erie blooms will be used to identify high-priority gene clusters for further biochemical studies via heterologous biosynthetic pathway expression in genetically tractable host organisms. A next-generation graph database will be developed to facilitate the synthesis and integrated queries of genetic, experimental, and environmental data. This project directly addresses two research priorities listed in the COHH3 RFA: (1) discovery of new toxins, (2) interrogation of how climate change impacts toxic algal blooms. A broader outcome will be the development of a versatile and high throughput approach to identify natural products from varied sources of secondary metabolite gene clusters through the integration of breakthrough technologies in high throughput metagenomics and bioinformatics with experimental and analytical laboratory approaches. This research project will be carried out by three labs that have a track record of close collaboration. It will be tightly integrated into the activities of the proposed center, drawing on infrastructure and resources provide by the center and providing a number of unique capabilities to the center.

摘要：新毒素的发现和表征 蓝藻有害藻华 (cHAB) 中常见的微囊藻和其他蓝藻 拥有众多编码多种未知天然产物生物合成的基因簇。这 项目将测试这些基因簇负责产生各种未知物质的假设 威胁人类和环境健康但目前仍看不见的毒素和生物活性化合物 水质评价常用的方法。目标是识别新的毒素及其特定的基因 通过研究纯培养物和未培养物的联合体进行生物合成和调节的途径 微生物。基因组将由宏基因组和占主导地位的代表性文化组装而成 形成水华的蓝藻物种。基因组和宏基因组的高通量生物信息学挖掘 将确定手动管理和结构预测的目标并确定优先级。与这些基于基因的平行 研究、培养物和现场样本分析将通过 (i) 对各种 密歇根大学化学基因组学中心的生物活性，以及​​ (ii) 代谢组学研究（由 Wilhelm 进行） 和博耶组），以及（iii）评估与人类疾病相关的潜在生物目标。综合起来， 关于伊利湖水华的遗传/生化新颖性、丰度和基因表达的结果将是 用于通过异源生物合成途径识别高优先级基因簇以进行进一步的生化研究 在遗传易处理的宿主生物体中表达。将开发下一代图形数据库 促进遗传、实验和环境数据的合成和综合查询。 该项目直接解决 COHH3 RFA 中列出的两个研究重点：(1) 发现新的 毒素，(2) 探讨气候变化如何影响有毒藻华。更广泛的成果将是 开发一种多功能、高通量的方法来识别不同来源的天然产物 通过高通量突破性技术的整合实现次生代谢基因簇 宏基因组学和生物信息学以及实验和分析实验室方法。本研究项目 将由三个有着密切合作记录的实验室进行。它将紧密地融入 拟议中心的活动，利用该中心提供的基础设施和资源，并提供 该中心拥有许多独特的功能。