Role of SRY in transgenerational transmission of alcohol epigenetic marks on proopiomelanocortin gene
SRY在阿黑皮素原基因酒精表观遗传标记跨代传递中的作用
基本信息
- 批准号:9382377
- 负责人:
- 金额:$ 34.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-01 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAlcohol consumptionAlcohol-Related DisordersAlcoholsAnimal ModelAnimalsBehavioralBindingBinding SitesBiological MarkersChildComplexCorticosteroneDNADataDevelopmentDiseaseDrug abuseDrug usageElectroporationEmotional DisturbanceEndocrineEnvironmental Risk FactorEpigenetic ProcessEthanolExcisionFertilizationFetal Alcohol ExposureFetal Alcohol Spectrum DisorderFetal Alcohol SyndromeFetal alcohol effectsGametogenesisGene ExpressionGene Expression RegulationGenerationsGenesGeneticGenomic DNAGerm CellsGrantGrowthHealthHeritabilityHormonesHumanHypothalamic structureImmuneImmune System DiseasesImmune System and Related DisordersImmune responseInbred F344 RatsInterferon Type IIInterferonsKnowledgeLearning DisabilitiesLifeLinkMalignant NeoplasmsMediatingMedicalMethodsMethylationModelingModificationMolecularMothersMutation AnalysisNational Institute on Alcohol Abuse and AlcoholismNeuropeptidesNeurosecretory SystemsPOMC geneParentsPatientsPharmaceutical PreparationsPhenotypePlasmidsPopulationPro-OpiomelanocortinProcessProductionPromoter RegionsPublic HealthRattusReporterResearchRiskRodent ModelRoleSeriesStressTechniquesTestingThird Pregnancy TrimesterTissuesTransfectionVariantY Chromosomealcohol and other drugalcohol effectalcohol exposurebasebeta-Endorphinbiological adaptation to stresschromatin immunoprecipitationcytokinedemethylationdrug induced behaviorendophenotypeepidemiology studyexpression vectorfetalgrandparentimmune functionimmune system functionimprintin vivointerestknock-downmalemelanocortin receptormethylation patternnext generationnoveloffspringoverexpressionpeptide Bpreferenceprenatalpreventpromoterpyrosequencingresponsesexsperm cellsry Genestranscription factortransgenerational epigenetic inheritancetransmission processyoung adult
项目摘要
Project Summary/Abstract
Children and young adults who were exposed to alcohol during fetal life often show fetal alcohol spectrum
disorders (FASD) consisting of learning disabilities, emotional disturbances, stress abnormalities and immune
incompetence. Furthermore, some grandparents who had alcohol-related medical problems often had
grandchildren with a higher rate of fetal alcohol syndrome than those grandparents without alcohol-related
medical problems. Epidemiological studies also have shown association of paternal alcohol consumption with
deficiencies in offspring—effects which are typically found with maternal alcohol exposure. However, the
process underlying the heritability of alcohol-induced health issues is not clearly understood. Our recent
studies identified an epigenetic mechanism in the heritable effect of fetal alcohol on stress response
abnormalities and immune dysfunctions. These studies showed that the proopiomelanocortin (Pomc) gene,
which negatively controls the functions of the stress axis and stimulates the functions of the immune systems,
is hypermethylated while the response of stress axis hormones and the production of the cytokine interferon-γ
(IFN-γ) is dysregulated in fetal alcohol exposed offspring for three generations via the male germline. However,
the process by which these epigenetic variants induced by fetal alcohol are transmitted from parents to
offspring through multiple generations has not been established. We hypothesize that a transcription factor like
sex-determining region Y (SRY), which has significant control over Pomc gene expression, undergoes
heritable epigenetic modifications by fetal alcohol exposures that in turn modify the expression of the Pomc
gene and its endophenotypes. The objective of this proposal is to determine the heritable epigenetic effects of
alcohol exposure during the prenatal period on SRY-mediated Pomc gene expression and its endophenotypes,
i.e., the stress hormone response and IFN-γ production to an immune challenge, in isogenic Fischer 344 rats.
This research aim will be achieved by determining the relationship between the fetal alcohol epigenetic marks
on Pomc and its endophenotypes with the epigenetic marks on the Sry gene in the isogenic rat population in
three generations of offspring, studying the interaction between SRY and Pomc at the molecular level, and
evaluating whether increased methylation affects SRY interaction with the Pomc promoter and contributes to
fetal alcohol effects on Pomc and its endophenotypes. Various state of the art techniques will be employed
involving promoter methylation, promoter demethylation, promoter activity, mutational analysis, gene knock
down, in vivo electroporation for gene overexpression, and stress and immune response studies. These
studies will establish the process by which developmental alcohol exposure induces gene expression variants
in the offspring and how they are transmitted to next generations. Knowledge on the process involved in the
heritability of alcohol-induced epigenetic variants may help in establishing new biomarkers and novel
epigenetic-based therapies for many alcohol-related disorders.
项目总结/文摘
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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DIPAK KUMAR SARKAR其他文献
DIPAK KUMAR SARKAR的其他文献
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{{ truncateString('DIPAK KUMAR SARKAR', 18)}}的其他基金
Role of exosomes in ethanol-induced neurotoxicity
外泌体在乙醇诱导的神经毒性中的作用
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10095400 - 财政年份:2020
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$ 34.88万 - 项目类别:
Role of exosomes in ethanol-induced neurotoxicity
外泌体在乙醇诱导的神经毒性中的作用
- 批准号:
10473743 - 财政年份:2020
- 资助金额:
$ 34.88万 - 项目类别:
Role of exosomes in ethanol-induced neurotoxicity
外泌体在乙醇诱导的神经毒性中的作用
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10266778 - 财政年份:2020
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Targeting the Opioidergic and Adrenergic Systems to Control Breast Cancers
针对阿片能和肾上腺素能系统来控制乳腺癌
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10153710 - 财政年份:2017
- 资助金额:
$ 34.88万 - 项目类别:
Role of SRY in transgenerational transmission of alcohol epigenetic marks on proopiomelanocortin gene
SRY在阿黑皮素原基因酒精表观遗传标记跨代传递中的作用
- 批准号:
10190731 - 财政年份:2017
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Fetal alcohol, estrogen-regulated genes and prostate cancer
胎儿酒精、雌激素调节基因和前列腺癌
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8974973 - 财政年份:2015
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Fetal alcohol, estrogen-regulated genes and prostate cancer
胎儿酒精、雌激素调节基因和前列腺癌
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9107765 - 财政年份:2015
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Biology of the NK cell cytolytic activity rhythm
NK 细胞溶细胞活性节律的生物学
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7523544 - 财政年份:2009
- 资助金额:
$ 34.88万 - 项目类别:
Fetal Alcohol Effects on Circadian clocks and POMC
胎儿酒精对生物钟和 POMC 的影响
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7856010 - 财政年份:2009
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$ 34.88万 - 项目类别:
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7856036 - 财政年份:2009
- 资助金额:
$ 34.88万 - 项目类别:
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