Project 2: High Resolution Mutation Spectra and Multi-Omics for Deducing Etiology and Predicting Disease
项目2:高分辨率突变谱和多组学用于推断病因和预测疾病
基本信息
- 批准号:10687979
- 负责人:
- 金额:$ 48.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAffectAir PollutionAnimal ModelAnimalsBiologicalBiological MarkersCatchment AreaCell Culture SystemCell Culture TechniquesCell modelCellsCessation of lifeCharacteristicsChemical ExposureChemicalsCollaborationsCommunitiesComplex MixturesCustomDNA AdductionDNA AdductsDNA DamageDNA RepairDNA Repair GeneDNA sequencingDataData AnalysesData SetDetectionDimethylnitrosamineDiseaseDisease OutcomeDoseElderlyEmbryoEnvironmentEnvironmental ExposureEnvironmental Risk FactorEpidemiologyEtiologyExcisionExposure toFemaleFibroblastsGene ExpressionGeneticGenetic EngineeringGenetically Engineered MouseGenomicsGoalsHazardous ChemicalsHazardous SubstancesHealthHumanHuman GenomeIndividualIndustrializationInflammationInformaticsInterventionIntraperitoneal InjectionsInvestigationKineticsKnowledgeLearningMGMT geneMaineMalignant NeoplasmsMammalian CellMeasurableMethodsModelingMolecularMolecular EpidemiologyMusMutagensMutationMutation SpectraN-nitrosodimethylamineNitrosaminesNitroso CompoundsPassamaquoddy Tribe of MainePathologyPathway interactionsPatternPersonsPhenotypePhosphorylationPredispositionPreventionProbioticsProceduresProcessPropylaminesProtein AnalysisProteinsProteomeProteomicsPublic HealthRecordsRegimenResearchResolutionRiskRisk AssessmentRisk ReductionSamplingScreening procedureSignal Recognition ParticleSignal TransductionSiteSourceSuperfundSystemTechniquesTechnologyTestingThe Cancer Genome AtlasTissuesToxic Environmental SubstancesToxic effectToxicologyToxinTribal groupWaterWater PollutionWorkWorld Health Organizationanimationbiological systemsburden of illnesscarcinogenicitycommunity engagementdata managementdata streamsdisorder preventiondrinking waterearly onsetefficacy evaluationenvironmental chemicalgene environment interactiongenome integritygenotoxicityhigh throughput screeninghuman datahuman diseaseinsightmalemembermouse modelmultiple omicsnoveloverexpressionphosphoproteomicsprogramsremediationresponsescreeningstressorsuperfund chemicalsuperfund sitetooltoxicanttranscriptomicstumorwelfare
项目摘要
PROJECT SUMMARY/ABSTRACT – PROJECT 2
Exposure of people to single chemicals or mixtures at Superfund sites has unquestionably occurred. The
unanswered question addressed here is whether those exposures can be associated with measurable risks to
genome integrity or expression, which would provide biological plausibility to the argument that the chemicals in
the environment have affected human health and welfare. The compounds chosen for investigation were inspired
by engagement efforts with a local community containing a Superfund site and with Tribal groups in Maine.
Carcinogenic N-nitrosamines (e.g., N-nitrosodimethylamine or NDMA) as well as other toxicants are abundant
in both of our catchment areas. These agents have not been studied as mutagens or proteome disruptors at the
level of detail proposed here, and they certainly have not been subjected to the combined multi-omic scrutiny of
this Project taken together with Project 1 (DNA damage and gene-environment interactions). The technology of
Project 2 has five components: (a) We employ a genetically engineered panel of mice (Project 1) that responds
to environmental toxicants in a manner that reveals underlying mechanisms that confer susceptibility to a
toxicant. The pathway to toxicity involves disease initiation, concomitant complications such as tissue-destructive
inflammation, through end stage pathologies such as cancers. (b) We use a newly developed high-fidelity DNA
sequencing procedure that provides unprecedentedly high-resolution mutational spectra (HRMS); HRMS can be
used to identify chemical-specific mutational patterns resulting from environmental exposures. (c) We use a
unique proteomic platform that sensitively senses disruptions in thousands of nodes in signaling networks. (d)
We use a novel computational module via the Data Management and Analysis Core that quantitatively
compares HRMS and proteomic patterns from our models with the rapidly expanding human data sets of The
Cancer Genome Atlas Project (TCGA), other tumor sequencing efforts, and the growing body of knowledge of
proteomic patterns. (e) Lastly, we introduce mouse embryo fibroblast (MEF) lines isogenic with our mouse
models that can be used as high-throughput screening tools to help find genotoxic fractions in complex mixtures
(Projects 3 and 4). Our multi-omic approach centers on animal and cellular models, but we also look ahead to
application of these novel tools for molecular epidemiology and for disease prevention. Regarding the latter
possibility, the proteomic and mutagenic biomarkers we already see in our work can be immediately be used to
assess the efficacy of probiotic mitigation of disease, via our interactions with Project 1. Regarding contributions
to epidemiology, the distinctive mutational spectra we have already observed following NDMA exposure to
animals and cells could eventually become valuable early-onset biomarkers that portend later life diseases.
Taken together, this Project leverages basic studies on genomics, adductomics, gene expression, and systems
toxicology to provide practical tools that can help detect and mitigate human diseases caused by specific
environmental chemicals that both our community partners and regulators have defined as agents of concern.
项目摘要/摘要-项目2
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JOHN M ESSIGMANN其他文献
JOHN M ESSIGMANN的其他文献
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{{ truncateString('JOHN M ESSIGMANN', 18)}}的其他基金
Project 2: High Resolution Mutation Spectra and Multi-Omics for Deducing Etiology and Predicting Disease
项目2:高分辨率突变谱和多组学用于推断病因和预测疾病
- 批准号:
10351933 - 财政年份:2017
- 资助金额:
$ 48.05万 - 项目类别:
Core D: Research Experience and Training Coordination Core
核心 D:研究经验和培训协调核心
- 批准号:
10688032 - 财政年份:2017
- 资助金额:
$ 48.05万 - 项目类别:
Core D: Research Experience and Training Coordination Core
核心 D:研究经验和培训协调核心
- 批准号:
10351939 - 财政年份:2017
- 资助金额:
$ 48.05万 - 项目类别:
Science and Engineering for Sensors, Mechanisms, and Biomarkers of Exposures
传感器、机制和暴露生物标志物的科学与工程
- 批准号:
9259573 - 财政年份:2017
- 资助金额:
$ 48.05万 - 项目类别:
The Environment as a Variable to Calibrate Mouse Models of Human Disease
环境作为校准人类疾病小鼠模型的变量
- 批准号:
7351205 - 财政年份:2008
- 资助金额:
$ 48.05万 - 项目类别:
The Environment as a Variable to Calibrate Mouse Models of Human Disease
环境作为校准人类疾病小鼠模型的变量
- 批准号:
8577178 - 财政年份:2008
- 资助金额:
$ 48.05万 - 项目类别:
The Environment as a Variable to Calibrate Mouse Models of Human Disease
环境作为校准人类疾病小鼠模型的变量
- 批准号:
8727548 - 财政年份:2008
- 资助金额:
$ 48.05万 - 项目类别:
The Environment as a Variable to Calibrate Mouse Models of Human Disease
环境作为校准人类疾病小鼠模型的变量
- 批准号:
8895929 - 财政年份:2008
- 资助金额:
$ 48.05万 - 项目类别:
The Environment as a Variable to Calibrate Mouse Models of Human Disease
环境作为校准人类疾病小鼠模型的变量
- 批准号:
8212454 - 财政年份:2008
- 资助金额:
$ 48.05万 - 项目类别:
The Environment as a Variable to Calibrate Mouse Models of Human Disease
环境作为校准人类疾病小鼠模型的变量
- 批准号:
8005036 - 财政年份:2008
- 资助金额:
$ 48.05万 - 项目类别:
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