Lupus Association with Signal Transducer and Activator of Transcription 4
狼疮与信号转导器和转录激活器的关联 4
基本信息
- 批准号:8598799
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-10-01 至 2016-09-30
- 项目状态:已结题
- 来源:
- 关键词:African AmericanAllelesAutoimmunityAwardBindingBiologicalCellsChromosome MappingCrohn&aposs diseaseCurcuminDNA MethylationDNA SequenceDataDiagnosisDiseaseEpigenetic ProcessEtiologyFacultyGene ExpressionGenesGeneticGenomicsGenotypeHaplotypesHispanicsHistonesImmune System DiseasesIn VitroInflammatoryInflammatory ResponseInformaticsInsulin-Dependent Diabetes MellitusInterferonsInterventionIntronsKnowledgeLentivirus VectorLifeLinkage DisequilibriumLiteratureLupusMapsMediatingMessenger RNAMethodologyMethodsMicroRNAsMilitary PersonnelMinorityMissionModificationMolecularPathogenesisPopulationProductionProteinsRNA analysisRegulationResearchRheumatoid ArthritisRiskRoleSTAT4 geneSTAT4 proteinStimulusSystemic Lupus ErythematosusTestingTherapeuticTimeVariantdesigndisorder riskgenetic risk factorgenetic varianthigh riskimprovedinhibitor/antagonistinsightnew technologynovelnovel therapeuticsphysical mappingprogramspublic health relevanceresearch studyresponserisk variantsmall hairpin RNAtranscription factor
项目摘要
DESCRIPTION (provided by applicant):
Of the many genes recently discovered to be associated with Systemic Lupus Erythematosus the haplotype in STAT4 is among the most powerful outside the HLA region. STAT4 is an important inflammatory transcription factor with the level in the cell determining the magnitude of
the response to the genes that STAT4 controls. This association is curious because it is localized in the fourth intron and the biological relevance of the relationship of this piece of DN to the function or activity of STAT4 is poorly understood. Our preliminary together with recent literature show that the risk allele expresses a higher level of STAT4 mRNA and protein and leads to increased sensitivity to Interferon-¿ (IFN-¿). The variant causing the association with lupus in STAT4 is located in a 55.5kb haplotype. DNA sequencing has defined many differences between the risk and non-risk haplotype. We will incorporate new genotyping and DNA sequencing data available and now being generated into a complete map, defining the genomic boundaries containing the causal variant(s) and identifying all of the possible variants that could
contribute to disease risk and reducing the interval (Aim 1). Next, since disease risk appears to be related to expression, we will explore sequence specific epigenetic alterations in histone marks and DNA methylation to identify the regions of the risk haplotype that are poised for increased STAT4 mRNA production (Aim 2). This will be a novel application of epigenetics for allele specific gene mapping and candidate causal variant identification that if successful will have general application for identifying gene variants that change disease risk by changing expression level. We will evaluate the hypothesis that the differential binding of transcription factors are responsible for the difference in STAT4 gene expression with informatic approaches to identify potential risk haplotype differences controlling gene expression and by applying in vitro methods to establish which of the identified variants is actually responsible for the change in gene expression (Aim 3). We anticipate identifying the causal variant in STAT4 and explaining some of the important details of the mechanism that generates risk for lupus. Finally, throughout the proposed program of research on STAT4 we will explore progressively more sophisticated strategies for decreasing the increased STAT4 activity in the risk haplotype (Aim 4). Initially, we will explore the potential impact on STAT4 activity with the known inhibitors (lisopfylline, curcumin, and statins). Later in the program and after we identify candidate causal transcription factors, we will deliver specific shRNA with lentivirus vectors to inhibit the actionof the candidate causal transcription factor(s), which may have the potential to reduce the increased STAT4 expression of the risk allele, returning the level of expression of the risk haplotype close to the STAT4 expression of the non-risk allele and, thereby, reducing the risk of lupus. STAT4 also is associated with rheumatoid arthritis, Crohn's disease, and type 1 diabetes, giving broad importance to any effort to understand STAT4 mechanism in autoimmunity, especially if this knowledge were to bring us closer to more effective and specific therapies for the immune dysfunction of these diseases.
描述(由申请人提供):
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 Barker Harley其他文献
John Barker Harley的其他文献
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{{ truncateString('John Barker Harley', 18)}}的其他基金
Lupus Association with Signal Transducer and Activator of Transcription 4 (STAT4)
狼疮与信号转导器和转录激活剂 4 (STAT4) 的关联
- 批准号:
9898284 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Better Outcomes for Children: Promoting Excellence in Healthcare Genomics to Inform Policy
为儿童带来更好的结果:促进卓越的医疗基因组学为政策提供信息
- 批准号:
9134798 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Better Outcomes for Children: Promoting Excellence in Healthcare Genomics to Inform Policy
为儿童带来更好的结果:促进卓越的医疗基因组学为政策提供信息
- 批准号:
9901995 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Better Outcomes for Children: Promoting Excellence in Healthcare Genomics to Inform Policy
为儿童带来更好的结果:促进卓越的医疗基因组学为政策提供信息
- 批准号:
9358502 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Better Outcomes for Children: Promoting Excellence in Healthcare Genomics to Inform Policy
为儿童带来更好的结果:促进卓越的医疗基因组学为政策提供信息
- 批准号:
9515026 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Better Outcomes for Children: GWAS & PheWAS in eMERGEII.
为儿童带来更好的结果:GWAS
- 批准号:
8469536 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Better Outcomes for Children: GWAS & PheWAS in eMERGEII.
为儿童带来更好的结果:GWAS
- 批准号:
8516741 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Lupus Association with Signal Transducer and Activator of Transcription 4
狼疮与信号转导器和转录激活器的关联 4
- 批准号:
8327991 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Lupus Association with Signal Transducer and Activator of Transcription 4
狼疮与信号转导器和转录激活器的关联 4
- 批准号:
8963456 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Lupus Association with Signal Transducer and Activator of Transcription 4
狼疮与信号转导器和转录激活器的关联 4
- 批准号:
8762443 - 财政年份:2012
- 资助金额:
-- - 项目类别:
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