Epigenetic Regulation of Immune Pathways in Sarcoidosis
Epigenetic Regulation of Immune Pathways in Sarcoidosis
批准号:
10200129
负责人:
LISA A MAIER
金额:
$69.76万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-07-01 至 2023-06-30
关键词:
AffectAllelesAntigen PresentationAntigen-Presenting CellsAntigensAreaAzacitidineBiologicalBiological MarkersBlood CellsBronchoalveolar LavageCD4 Positive T LymphocytesCase-Control StudiesCell Differentiation processCellsCessation of lifeChronicCicatrixCritical PathwaysDNA MethylationDataDecitabineDevelopmentDiseaseDisease remissionEducational workshopEnvironmentEnvironmental ExposureEpigenetic ProcessEvaluationExposure toFOXP3 geneFolic AcidFutureGene ExpressionGenesGeneticGenetic Predisposition to DiseaseGenetic TranscriptionGenomeGenomic approachGenomicsGoalsGranulomaGranulomatousHLA-DRB1HealthHeritabilityImmuneImmune Response GenesImmune responseImmunophenotypingIndividualInhalationLifeLightLungLung diseasesMAP Kinase GeneMediatingMethylationModificationMorbidity - disease rateNational Heart, Lung, and Blood InstituteNatural HistoryOther GeneticsPathogenesisPathogenicityPathway interactionsPhenotypePredispositionPrevalenceProgressive DiseaseProliferatingPulmonary SarcoidosisRaceRegulationResearchResolutionRiskRisk FactorsSamplingSarcoidosisSignal PathwaySiteT-Cell ReceptorT-LymphocyteTestingUnderserved PopulationValidationVariantbasechemokinecohortcytokinedisease phenotypedisorder riskepigenetic regulationgenetic variantgenome-widehistone modificationhuman subjectimmunoregulationnon-smokernovelpotential biomarkerprogramspublic health relevancepyrosequencingrecruittargeted treatmenttherapeutic target
中文摘要
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英文摘要
PROJECT SUMMARY/ABSTRACT
The goal of this study is to define the epigenetic marks and their impact on gene expression that result in the
granulomatous lung disease, sarcoidosis, and two of the most common sarcoidosis phenotypes, progressive
pulmonary disease and remitting disease. The study relies on the expertise and strengths of our uniquely
qualified investigative team. It will define pathogenic pathways and risk factors for sarcoidosis and two common
phenotypes of disease, and have implications for similar immune mediated diseases. In sarcoidosis, it appears
that exposure to an unknown inhaled antigen(s) in the setting of a genetically susceptible host, initiates a Th1
immune response, with antigen presentation occurring via HLA Class II on antigen presenting cell (APC) in the
context of CD4+ T cells. Subsequently, CD4+ T cells and APCs are recruited to the lung, proliferate, produce
cytokines and chemokines, and eventually form granulomas. An increased prevalence of HLA-DRB1 alleles is
found in sarcoidosis, although the exact alleles vary based on an individual's race, ethnic background and
disease phenotype. There are a limited number of other genetic variants associated with sarcoidosis, suggesting
that other susceptibility factors or forms of genetic regulation must be important in disease pathogenesis.
Growing data in other lung diseases suggests that epigenetic mechanisms in combination with genetic
susceptibility and environment may help explain disease risk. Epigenetic modifications determine the Th1 versus
Th2 immune response through DNA methylation and histone modifications of key genes such as FOXP3, and
thus impact health and disease. To date epigenetic alterations have not been explored in sarcoidosis. Our
preliminary data demonstrate significant genome-wide DNA methylation differences in pivotal immune response
genes and networks at the site of exposure and disease, the lung, in sarcoidosis compared to subjects without
granulomatous lung disease. Based on this information, the overarching hypothesis for this proposal is that DNA
methylation changes in genes in key immune pathways impact gene expression and immune cell
differentiation, and thus risk of sarcoidosis. Using an integrated genomic approach we will first define
epigenetic alterations in CD4+ lung cells, in a case control study of sarcoidosis cases with progressive and
remitting disease and normal controls. Subsequently, we will determine functional methylation alterations that
impact gene transcription, information which will expand our understanding of the pathogenesis of sarcoidosis.
As demethylating agents, such as 5-azacytidine (AZA) and decitabine are currently being used to treat immune
mediated diseases, we will evaluate changes in validated methylation and gene expression targets treating
sarcoidosis CD4+ lung cells with demethylating (AZA) or methylating (folic acid) agents. This study will provide
data relevant to this class of agents as targets for therapy. Furthermore, the information gained from this proposal
will shed light on the pathogenesis of sarcoidosis and its phenotypes and on genome-exposure relationships.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1183/16000617.0076-2021
发表时间:
2021-06-30
期刊:
EUROPEAN RESPIRATORY REVIEW
影响因子:
7.5
作者:
[Konigsberg, Iain R., Maier, Lisa A., Yang, Ivana, V]
通讯作者:
Yang, Ivana, V
Using Multi-Omics to Define Regulators and Drivers of Granulomatous Inflammation and Chronic Beryllium Disease
-
批准号:10569103
-
项目类别:
-
资助金额:$64.77万
-
财政年份:2022
-
负责人:LISA A MAIER
-
依托单位:
Using Multi-Omics to Define Regulators and Drivers of Granulomatous Inflammation and Chronic Beryllium Disease
-
批准号:10339740
-
项目类别:
-
资助金额:$65.96万
-
财政年份:2022
-
负责人:LISA A MAIER
-
依托单位:
Aspen Lung Conference: Environment and Global Lung Health, Susceptibility, and Intervention
-
批准号:9327639
-
项目类别:
-
资助金额:$3.0万
-
财政年份:2017
-
负责人:LISA A MAIER
-
依托单位:
Exposure in Epigenetic Regulation of Immune Response in CBD
-
批准号:9197647
-
项目类别:
-
资助金额:$44.85万
-
财政年份:2015
-
负责人:LISA A MAIER
-
依托单位:
Exposure in Epigenetic Regulation of Immune Response in CBD
-
批准号:8816361
-
项目类别:
-
资助金额:$42.57万
-
财政年份:2015
-
负责人:LISA A MAIER
-
依托单位:
Project 2 - Immunogenetic and Exposure Factors in Berylliosis
-
批准号:8382597
-
项目类别:
-
资助金额:$42.31万
-
财政年份:2012
-
负责人:LISA A MAIER
-
依托单位:
Immunologic and Molecular Phenotypes in AATD and Sarcoidosis
-
批准号:8264826
-
项目类别:
-
资助金额:$15.85万
-
财政年份:2012
-
负责人:LISA A MAIER
-
依托单位:
Immunologic and Molecular Phenotypes in AATD and Sarcoidosis
-
批准号:8464231
-
项目类别:
-
资助金额:$15.09万
-
财政年份:2012
-
负责人:LISA A MAIER
-
依托单位:
Immunologic and Molecular Phenotypes in AATD and Sarcoidosis
-
批准号:8662308
-
项目类别:
-
资助金额:$15.53万
-
财政年份:2012
-
负责人:LISA A MAIER
-
依托单位:
Project 2 - Immunogenetic and Exposure Factors in Berylliosis
-
批准号:7714445
-
项目类别:
-
资助金额:$47.45万
-
财政年份:2009
-
负责人:LISA A MAIER
-
依托单位:
BERYLLIUM RESEARCH PROGRAM, PROJECT 1
-
批准号:7719386
-
项目类别:
-
资助金额:$0.02万
-
财政年份:2008
-
负责人:LISA A MAIER
-
依托单位:
USE OF SPUTUM AND ENVIRONMENTAL TESTING FOR CBD SURVEILLANCE AND MONITORING
-
批准号:7719406
-
项目类别:
-
资助金额:$0.12万
-
财政年份:2008
-
负责人:LISA A MAIER
-
依托单位:
BERYLLIUM RESEARCH PROGRAM, PROJECT 2
-
批准号:7719387
-
项目类别:
-
资助金额:$0.01万
-
财政年份:2008
-
负责人:LISA A MAIER
-
依托单位:
CLINICAL EFFICACY OF REMICADE IN CBD
-
批准号:7719391
-
项目类别:
-
资助金额:$0.06万
-
财政年份:2008
-
负责人:LISA A MAIER
-
依托单位:
BERYLLIUM RESEARCH PROGRAM, PROJECT 1
-
批准号:7604341
-
项目类别:
-
资助金额:$0.17万
-
财政年份:2007
-
负责人:LISA A MAIER
-
依托单位:
CLINICAL EFFICACY OF REMICADE IN CBD
-
批准号:7604348
-
项目类别:
-
资助金额:$1.62万
-
财政年份:2007
-
负责人:LISA A MAIER
-
依托单位:
Shared Genetic Susceptibility in CBD and Sarcoidosis
-
批准号:7211940
-
项目类别:
-
资助金额:$28.24万
-
财政年份:2007
-
负责人:LISA A MAIER
-
依托单位:
BERYLLIUM RESEARCH PROGRAM, PROJECT 2
-
批准号:7604342
-
项目类别:
-
资助金额:$0.17万
-
财政年份:2007
-
负责人:LISA A MAIER
-
依托单位:
Shared Genetic Susceptibility in CBD and Sarcoidosis
-
批准号:7352773
-
项目类别:
-
资助金额:$16.01万
-
财政年份:2007
-
负责人:LISA A MAIER
-
依托单位:
APOPTOSIS-RELATED GENETIC POLYMORPHISMS IN SARCOIDOSIS
-
批准号:7377731
-
项目类别:
-
资助金额:$0.56万
-
财政年份:2006
-
负责人:LISA A MAIER
-
依托单位:
海外基金