Non-Coding Variants of Angiotensinogen Gene and Hypertension
血管紧张素原基因的非编码变异与高血压
基本信息
- 批准号:9325162
- 负责人:
- 金额:$ 37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2019-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdipose tissueAllelesAngiotensin IIAngiotensinogenAnimalsBase SequenceBindingBinding SitesBiological AssayBlood PressureCarbohydratesChromatinCpG dinucleotideDNADNA MethylationEnhancersExonsFamilyFatty acid glycerol estersFemaleGenesGenomeHaplotypesHeart failureHepatocyteHumanHypertensionIndiumIndividualInflammationIntronsKidneyKidney FailureKnock-inLiverMolecularMusMyocardial InfarctionNucleotidesOrganOxidative StressPlayProcessProteinsReninRenin-Angiotensin SystemReporterRisk FactorsRoleSodium ChlorideStrokeTissuesTranscriptional RegulationTransfectionTransgenic AnimalsTransgenic MiceUntranslated RNAUntranslated RegionsVariantVascular Diseasesbaseblood pressure regulationchromatin immunoprecipitationchromosome conformation capturegenome wide association studyhigh salt dietinflammatory markerkidney cellmalepromoterpublic health relevancetranscription factorwestern diet
项目摘要
DESCRIPTION (provided by applicant): Hypertension is a serious risk factor for myocardial infarction, heart failure, vascular disease, stroke, and renal failure. The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure (BP). Recent genome wise association studies (GWAS) have shown that an A/G SNP (rs2004776) located at +1164 in intron-I of the human angiotensinogen (hAGT) gene is associated with hypertension. The nucleotide sequence of hAGT gene containing +1164A allele has stronger homology with HNF-3 binding site as compared to +1164G. HNF3 family belongs to "pioneer" transcription factors whose binding to promoters and enhancers enables chromatin access for other tissue-specific transcription factors. SNPs in the promoter and intron I of the hAGT gene can be divided in 2 major haplotypes: haplotype-I (containing +1164A) and II (containing +1164G). Nucleotide variants in haplotype-I bind more strongly to transcription factors as compared to haplotype-II and reporter construct containing haplotype-I has increased promoter activity as compared to haplotype-II on transient transfection. Transgenic mice containing either haplotype-I or II of the hAGT gene were generated by knock-in approach at the HPRT locus. Preliminary studies have shown that: (a) CpG dinucleotides in the hAGT promoter of TG mice containing haplotype- I are hypo-methylated and accessible to transcription factors as compared to haplotype-II, (b) male TG mice containing haplotype-I have increased basal and GR induced expression of the hAGT gene in liver, kidney and fat as compared to haplotype-II, (c) chromatin from liver and kidney of transgenic animals containing haplotype-I binds more strongly to HNF3β, C/EBPβ, STAT-3 and GR as compared to haplotype-II, (d) double TG mice containing hREN gene and haplotype-I of the hAGT gene have increased BP as compared to haplotype-II which is further increased by Western diet containing high carbohydrate: high fat: high salt diet. In the present application, th role of SNP at +1164 and other cis-acting DNA elements in intron-I on transcriptional regulation of the hAGT gene will be analyzed by DNA methylation assay, chromosome conformation capture (3C) assay, ChIP assay and transient transfection assay. The effect of Western diet on the expression of the hAGT gene, blood pressure regulation, and end organ damage will be analyzed using male/female double transgenic mice containing hREN gene and either haplotype-I or haplotype-II of the hAGT gene.
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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ASHOK KUMAR其他文献
ASHOK KUMAR的其他文献
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$ 37万 - 项目类别:
Non-Coding Variants of Angiotensinogen Gene and Hypertension
血管紧张素原基因的非编码变异与高血压
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