Interaction between Genome and Heavy Metals in Nonalcoholic Fatty Liver Disease
非酒精性脂肪肝中基因组与重金属的相互作用
基本信息
- 批准号:10658148
- 负责人:
- 金额:$ 63.1万
- 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:2023-06-15 至 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAffectAgeAlcohol consumptionAllelesAreaBioinformaticsBiological AssayBiopsyBiopsy SpecimenCellsCharacteristicsChildChromatinChronicClinicalCollaborationsCollectionCommunitiesComplexDataData AnalysesDepositionDevelopmentDiabetes MellitusDiseaseEnvironmentEnvironmental ExposureEnvironmental Risk FactorExposure toFDA approvedFibrosisFosteringFreezingGene ExpressionGenesGenetic RiskGenomeGenotypeGoalsHealth systemHeavy MetalsHepatocyteHistologicHistologyHumanImmuneIndividualIndustrializationInterventionKnowledgeLiverLiver CirrhosisMalignant neoplasm of liverMapsMediatingMetabolic DiseasesMetabolismMetal exposureMetalsMichiganModelingMolecularMolecular TargetMultiomic DataObesityPathogenesisPathologicPathway interactionsPatientsPerfusionPharmaceutical PreparationsPharmacotherapyPopulationPredispositionPreparationPreventionPreventiveQuantitative Trait LociResearchRiskRoleSeveritiesStatistical ModelsTestingTherapeuticTimeTissuesTransposaseValidationVariantZincagedcell typechronic liver diseasecohortdisease diagnosisdisorder preventiondisorder riskdrug discoverygenetic makeupgenetic risk factorgenetic variantgenome wide association studygenome-widegenome-wide analysishigh riskinsightliver biopsyliver transplantationmetropolitannon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelnovel diagnosticsprotective effectresponserisk variantsingle-cell RNA sequencingsocialstellate celltooltranscriptometranscriptome sequencingtranscriptomics
项目摘要
ABSTRACT
The ultimate goal of this project is to discover and validate the gene Х heavy metal (GXM) interactions in
human livers and to understand their role in nonalcoholic fatty liver disease (NAFLD). NAFLD is the most
common chronic liver disease affecting over 30% of the U.S population, resulting in a heavy social burden.
NAFLD is characterized by a spectrum of histological changes with multiple cells involved. Currently, no
approved drug treatment is available for NAFLD. Therefore, it is an urgent need to identify both genetic and
environmental risk factors to facilitate the development of new diagnostic, preventive, and therapeutic
strategies. NAFLD is a typical complex disease involving gene-environment (GXE) interactions. Over the past
decade, while GWAS for NAFLD have identified numerous genetic risk alleles, a growing body of research has
demonstrated that exposure to heavy metals (Pb, Cd, Hg, As, etc.) are associated with increased NAFLD risk.
However, there is no compelling study thus far to assess the correlation between various naturally
accumulated metals in human livers and the NAFLD histology, especially in clinically defined patient cohorts.
More importantly, there lacks critical knowledge about how naturally and chronically accumulated metals
interact with the liver genome and together confer risks for NAFLD. Our preliminary studies in human liver
tissues have successfully demonstrated that multiple metals are indeed correlated with NAFLD. By leveraging
our previously collected multi-omics data, we have preliminarily identified numerous metal-response genes
(MR-genes), expression quantitative traits loci (eQTLs), and allele-specific expression loci (ASEs), which are
further enriched to NAFLD and its related pathways. We aim in this study to further expand our study to a
large-scale, highly detailed, and integrated analysis to thoroughly understand the role of GXM interactions in
NAFLD in humans. To this end, our team has been collaborating to establish collections for human liver tissue,
cells and NAFLD patient cohorts. We have also developed various technical platforms e.g. bulk/single cell (Sc)
RNAseq and ATAC-seq, as well as multiple bioinformatics and statistical tools for GXE data analyses. With
these preparations, we specifically aim: 1) To profile heavy metals in frozen human liver tissues (n=560),
identify MR-genes, eQTLs/ASEs, and test their associations with NAFLD; 2) To treat the primary liver cell
populations with various metals and to elucidate how the genome of different liver cells respond to metals with
Sc-RNAseq and ATAC-seq, and 3) To validate the association between GXM interactions and NAFLD
histology severity in a large clinically defined NAFLD patient cohort (n=1313). Our study will for the first time
evaluate the role and mechanism of GXM interactions in NAFLD and will provide the scientific community
important data to open new avenues to NAFLD research, drug discovery, and beyond.
摘要
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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Andrea E Cassidy-Bushrow其他文献
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