Transcriptional Responses to Wildfire Pollution in Airway Epithelial Cells Identify Genetic Risk Factors and Mechanisms of Asthma Exacerbations
气道上皮细胞对野火污染的转录反应确定了哮喘恶化的遗传风险因素和机制
基本信息
- 批准号:10573003
- 负责人:
- 金额:$ 17.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-12-17 至 2027-11-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAirAir PollutantsAir PollutionAllelesAryl Hydrocarbon ReceptorAsthmaBindingBinding SitesBioinformaticsBiological AssayCell Culture TechniquesCell LineCell modelChromatinClinicalClinical DataClustered Regularly Interspaced Short Palindromic RepeatsConsensusDexamethasoneDiseaseDisease modelEpithelial CellsFamilyGene ExpressionGenesGenetic PolymorphismGenetic TranscriptionGenomic DNAGenomicsGlucocorticoid ReceptorGrantHealthHousingHumanIL8 geneIndividualInflammationInterleukin-8LaboratoriesLiquid substanceLuciferasesMediatingMediatorMentorsMethodologyMethodsMinorModelingMorbidity - disease rateNF-kappa BParticulatePatientsPhysiologicalPlasmidsPollutionPopulation StudyPredispositionPublic HealthRecommendationRegulationRegulator GenesReporterRisk EstimateRoleSeriesSeveritiesSingle Nucleotide PolymorphismSmokeSusceptibility GeneSymptomsTechniquesTestingToxic effectVariantWildfireairway epitheliumassociated symptomasthma exacerbationbioinformatics toolclimate changeexperiencegenetic risk factorgenetic variantgenome editinghigh riskhuman tissuemortalitynext generation sequencingnovelparticleparticle exposurepharmacologicpollutantreceptor expressionresponsetherapeutic targettissue culturetooltranscription factorwood smoke
项目摘要
Project Summary/Abstract
Increased levels of air pollution from wildfires are directly associated with asthma exacerbations but
the mechanisms mediating this association are not understood. Furthermore, the severity of asthma
symptoms that result from wildfire exposure vary considerably by individual. We seek to identify
Transcriptional Regulatory Elements (TREs) that connect wildfire particulate exposures with genetic
variants associated with asthma to identify susceptibility features and mechanisms that govern asthma
exacerbations.
We will employ wood smoke particle (WSP) exposure in primary airway epithelial cells cultured at air-
liquid interface to model the interaction between the respiratory epithelium and fine particulates
released by wildfires. We will assay chromatin accessibility and nascent transcription using next-
generation sequencing techniques to identify TREs regulated by WSP. Then, using a permutation-
based bioinformatic approach, we will intersect the genomic coordinates of these TREs with genomic
susceptibility loci for asthma. We will then characterize the transcriptional function of single nucleotide
polymorphisms (SNPs) that result from this intersection. We will test TRE function in the context of
WSP exposure with and without the SNPs in plasmid-derived luciferase reporters and in genomic
DNA, using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) – Cas9 tool to
introduce the variant alleles. Finally, to assay the physiologic significance of these TRE-SNP overlaps,
we will test the role of the rs258760 SNP, which inhabits a TRE under regulation by WSP and controls
expression of the glucocorticoid receptor, in mediating Interleukin-8 secretion by exposing airway
epithelial cells from donors with the major and minor alleles to WSP and dexamethasone.
This project will identify and characterize genomic features that connect air pollution with asthma
exacerbations. These loci and the genes they regulate will serve as candidates for pharmacologic
therapies to mitigate asthma symptoms associated with wildfire air pollution. Furthermore, this
project develops a method to integrate multiple models of disease in a genomic context. This
strategy may be used to propose novel treatments for asthma.
项目摘要/摘要
野火造成的空气污染水平增加与哮喘恶化直接相关,但
调解这种联系的机制还不清楚。此外,哮喘的严重程度
暴露在野火中的症状因人而异。我们试图找出
转录调控元件(TRE)将野火颗粒物暴露与基因
与哮喘相关的变异以确定哮喘的易感性特征和机制
病情加重。
我们将在空气中培养的原代呼吸道上皮细胞中使用木烟颗粒(WSP)暴露-
模拟呼吸道上皮和细颗粒之间相互作用的液体界面
在野火中被释放。我们将使用Next-来分析染色质的可及性和新生转录。
用于识别受WSP调控的TRE的世代测序技术。然后,使用一种排列-
基于生物信息学的方法,我们将这些tre的基因组坐标与基因组相交。
哮喘的易感基因。然后我们将描述单核苷酸的转录功能。
从这个交叉点产生的多态(SNP)。我们将在以下上下文中测试TrE函数
携带和不携带SNPs的WSP在质粒源荧光素酶报告基因和基因组中的暴露
DNA,使用聚类规则间隔短回文重复(CRISPR)-Cas9工具
介绍变异等位基因。最后,为了分析这些tre-SNP重叠的生理意义,
我们将测试rs258760 SNP的作用,它居住在WSP和Controls的监管下的tre
糖皮质激素受体在暴露呼吸道介导白介素8分泌中的表达
具有WSP和地塞米松主次等位基因的供体上皮细胞。
该项目将识别和描述将空气污染与哮喘联系起来的基因组特征。
病情加重。这些基因座及其调控的基因将成为药理学的候选基因。
缓解与野火空气污染相关的哮喘症状的治疗方法。此外,这一点
该项目开发了一种在基因组环境中整合多种疾病模型的方法。这
该策略可用于提出治疗哮喘的新方法。
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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