Shifting paradigms to emerging toxins in freshwater cyanobacterial blooms
淡水蓝藻水华中新出现的毒素的范式转变
基本信息
- 批准号:10912318
- 负责人:
- 金额:$ 19.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAcuteAcute Liver FailureAffectAlkaloidsAmino AcidsAnatoxinsAnimalsArginineArtificial MembranesBiological AssayBiological AvailabilityBiomassBiomimeticsBrainCell Membrane PermeabilityChemicalsChronicCollectionCommunitiesComplexCyanobacteriumCyanotoxinCytotoxinDataDetectionEnvironmentEnvironmental HealthEvaluationEventExposure toFatty LiverFresh WaterGeneticGoalsHarvestHealthHepatocyteHepatotoxicityHumanImageIn VitroIndividualInjuryInvertebratesKidneyKnowledgeLaboratoriesLactonesLeucineLiverMediatorMembraneMethodsMicrobeMicrocystisMissionMolecularMonitorNatural ResourcesNeurotoxinsNew EnglandPeptidesPermeabilityPharmacologic SubstancePhosphoric Monoester HydrolasesPoisonPolicy MakerPopulationProductionProteomicsPublic HealthRecreationRegulationReproductive systemResearchResearch Project GrantsResourcesRhode IslandRiskRodentRoleSamplingSaxitoxinScreening procedureSiteStructureSystemSystemic diseaseTaxonomyTestingTimeToxic effectToxicologyToxinTyrosineUnited StatesUnited States National Institutes of HealthVertebratesWaterWorkWritingacute hepatotoxicitybioaccumulationclimate changecontaminated drinking watercyanobacterial toxincyanoginosin LRcylindrospermopsincytotoxicdrinking waterexposed human populationharmful algal bloomshepatotoxinin silicoin vivoindustry partnerinnovationinsightinstrumentationliver injurylocal economymembermetabolomemetabolomicsmicrobial communitymicrocystinnon-alcoholic fatty liver diseasenovelsuccesstemporal measurementtoolvector
项目摘要
PROJECT SUMMARY
Cyanobacterial harmful algal blooms (cyanoHABs) and the toxic compounds produced during these events have
become a persistent problem in freshwater systems and have affected local populations by contaminating
drinking water and placing a significant burden on local economies due to diminished recreational activity.
Microcystins, generally the dominant class of toxins in cyanoHABs, primarily affect the liver (hepatotoxin), but
have been described to also affect the kidney, the reproductive system, and the brain. Cyanobacteria in these
bloom events are known to produce a suite of hepatotoxins in addition to the microcystins such as the
cylindrospermopsins, and alkaloid neurotoxins such as saxitoxin and anatoxin. Preliminary results from the Bertin
Laboratory and collaborative industry partners in the proposed project, Biosortia Pharmaceuticals, have shown
exquisitely potent cytotoxins exist in environmental collections of cyanobacterial biomass harvested from inland
lakes and water bodies. A suite of these emerging compounds (steroidal lactones) departs significantly from the
types of toxic compounds typically associated with these bloom events (peptidic and alkaloidal toxins). These
newly discovered compounds are significantly more potent than microcystin-LR and have never been previously
described from cyanoHAB events. Thus, there is a significant and unmet need to understand the production of
these compounds and other cytotoxic metabolites during cyanoHABs and to develop detection, isolation, and
toxicological evaluation tools that can be utilized by natural resource management agencies and inform public
health policy makers. Furthermore, preliminary results indicate that there are new microcystins in cyanoHABs
that are significantly more cytotoxic than any of the 130 known microcystin congeners. The rationale of this
research project is that there needs to be a full accounting of the toxic chemical space present in cyanoHABs.
Furthermore, the diversity of multiple toxic compounds requires new evaluation tools to determine the most
potent cyanotoxins, their mode of action, and their potential toxicity on the liver and how that relates to systemic
injury. Project goals will consist of the identification and isolation of emerging toxic compounds using
metabolomics approaches, microbial community analysis, and the structure elucidation of emerging toxins (Aim
1). Furthermore, the toxin composition of cyanoHABs will be investigated in a time course study to provide
temporal resolution with respect to toxic metabolite composition (Aim 1). Next, a toxicological assessment will
be used that integrates in silico, in vitro, and proteomic studies to determine toxicity and the mechanism of action
of toxins (Aim 2). Instrumentation and expertise are in place for project success. This project will result in the
isolation and characterization of emerging toxins and significantly departs from the current status quo of focusing
on microcystins. Additionally, this work will develop an understanding of the mechanistic toxicity of these novel
emerging metabolites to potential liver injury, which can be an early mediator of systemic disease.
项目概要
蓝藻有害藻华 (cyanoHAB) 以及这些事件期间产生的有毒化合物已
成为淡水系统中一个持续存在的问题,并通过污染影响当地居民
由于娱乐活动减少,饮用水给当地经济带来了沉重负担。
微囊藻毒素通常是氰基HAB 中的主要毒素,主要影响肝脏(肝毒素),但
据描述,它也会影响肾脏、生殖系统和大脑。这些中的蓝藻
众所周知,除了微囊藻毒素外,水华事件还会产生一系列肝毒素,例如
圆柱精视素和生物碱神经毒素,例如石房蛤毒素和赤虾毒素。 Bertin 的初步结果
拟议项目中的实验室和合作行业合作伙伴 Biosortia Pharmaceuticals 已经表明
从内陆收获的蓝藻生物质的环境收藏中存在极其有效的细胞毒素
湖泊和水体。一系列新兴化合物(甾体内酯)与
通常与这些水华事件相关的有毒化合物类型(肽和生物碱毒素)。这些
新发现的化合物比微囊藻毒素-LR 更有效,并且以前从未有过
描述自cyanoHAB 事件。因此,了解生产的重要且未满足的需求
这些化合物和其他细胞毒性代谢物在氰基HABs期间,并开发检测、分离和
可供自然资源管理机构使用并告知公众的毒理学评估工具
卫生政策制定者。此外,初步结果表明,cyanoHAB 中存在新的微囊藻毒素
其细胞毒性明显高于 130 种已知微囊藻毒素同系物中的任何一种。这样做的理由
研究项目是需要对氰基HAB 中存在的有毒化学空间进行全面核算。
此外,多种有毒化合物的多样性需要新的评估工具来确定最
强效蓝藻毒素、其作用方式、对肝脏的潜在毒性及其与全身性的关系
受伤。项目目标将包括使用以下方法识别和分离新出现的有毒化合物:
代谢组学方法、微生物群落分析以及新兴毒素的结构阐明(Aim
1).此外,cyanoHAB 的毒素成分将在时间过程研究中进行调查,以提供
有毒代谢物成分的时间分辨率(目标 1)。接下来,将进行毒理学评估
用于整合计算机、体外和蛋白质组学研究以确定毒性和作用机制
毒素(目标 2)。仪器和专业知识已到位,以确保项目成功。该项目将导致
新兴毒素的分离和表征,与目前重点关注的现状有很大不同
关于微囊藻毒素。此外,这项工作将加深对这些新型药物的机械毒性的理解。
新出现的代谢物可能导致潜在的肝损伤,这可能是全身性疾病的早期介质。
项目成果
期刊论文数量(0)
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Matthew John Bertin其他文献
Matthew John Bertin的其他文献
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{{ truncateString('Matthew John Bertin', 18)}}的其他基金
Shifting paradigms to emerging toxins in freshwater cyanobacterial blooms
淡水蓝藻水华中新出现的毒素的范式转变
- 批准号:
10526727 - 财政年份:2022
- 资助金额:
$ 19.74万 - 项目类别:
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