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 在蓝细菌有害藻华（CHABS）中通常发现的微囊藻和其他蓝细菌 藏有许多编码不同天然产物和未知天然产物的生物合成的基因簇。这 项目将测试这些基因簇负责产生各种未知的假设 毒素和生物活性化合物威胁人类和环境健康，但目前仍然是看不见的 通常用于评估水质的方法。目的是识别新颖的毒素及其特定遗传 通过研究纯培养物和未培养的伴侣的生物合成和调节途径 微生物。基因组将来自宏基因组和主要的代表性培养 布鲁姆形成的蓝细菌物种。基因组和宏基因组的高通量生物信息开采 将识别并确定手动策划和结构预测的目标。与这些基于基因的平行 研究，分析培养物和现场样本将通过（i）高通量筛选分析多种 U-M化学基因组学中心和（ii）代谢组学研究（由Wilhelm进行） 和Boyer组）和（iii）评估与人类疾病有关的潜在生物学靶标。在一起， 关于伊利湖开花中基因的遗传/生化新颖性以及基因表达的结果将是 用于鉴定高优先性基因簇，以通过异源生物合成途径进行进一步的生化研究 在遗传诱导的宿主生物中的表达。下一代图数据库将开发为 促进遗传，实验和环境数据的合成和综合查询。 该项目直接解决了COHH3 RFA中列出的两个研究优先级：（1）发现新的 毒素，（2）对气候变化如何影响有毒藻类开花的审问。更广泛的结果将是 开发一种多功能和高吞吐量方法，以从各种来源识别天然产品 次生代谢产物基因簇通过在高吞吐量中的突破性技术的整合 实验和分析实验室方法的宏基因组学和生物信息学。这个研究项目 将由三个具有密切协作记录的实验室进行的。它将紧密整合到 拟议中心的活动，利用中心提供的基础设施和资源，并提供 中心有许多独特的功能。