Ah Receptor Anatomy: Implications for Dioxin Toxicity
Ah 受体解剖:对二恶英毒性的影响
基本信息
- 批准号:7746391
- 负责人:
- 金额:$ 32.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1996
- 资助国家:美国
- 起止时间:1996-03-01 至 2011-10-31
- 项目状态:已结题
- 来源:
- 关键词:AnatomyAryl Hydrocarbon ReceptorAuthorization documentationBindingBiological AssayBiological ProcessBromodeoxyuridineCDKN1B geneCancer CenterCell Culture TechniquesCell CycleCell LineCell ProliferationCellsChromatinCitiesComplexConsensusCyclinsDNADioxinsDisclosureEMSAElectrophoretic Mobility Shift AssayElementsExtracellular MatrixFaceFluorescenceFundingGene ExpressionGene TargetingGenerationsGenesGenetic TranscriptionGoalsGrowthGrowth FactorHepaticHepatocyteHomeostasisHumanHuman ResourcesInjuryInjury to LiverInstructionIonsLast NameLeadLigandsLiverLiver FailureLiver RegenerationMalignant neoplasm of liverMedicalModelingMolecularMusNamesNatural regenerationPartial HepatectomyPhosphotransferasesPlasminogenPlasminogen ActivatorPlasminogen Activator Inhibitor 1PlayPostdoctoral FellowPrincipal InvestigatorPrintingProcessProliferatingProteinsPyrenesRegistriesRegulationRelative (related person)ResearchResearch PersonnelResearch Project GrantsResponse ElementsRoleSerumSignal TransductionSiteSorting - Cell MovementTetrachlorodibenzodioxinTexasTimeTissuesToxic effectToxinTumor Suppressor ProteinsTweensUniversitiesUrokinaseVirus DiseasesWisconsinXenobioticsactivating transcription factoraryl hydrocarbon receptor ligandaryl hydrocarbonsautocrinebasechromatin immunoprecipitationdesignextracellularfetal bovine serumhuman CDK2 proteinhuman embryonic stem cellinhibitor/antagonistliver cell proliferationmouse Ahr proteinnovelparacrineprogramspromoterprotein degradationprototypereceptorreceptor bindingregenerativerepairedresearch studyresponseresponse to injuryretinoblastoma tumor suppressor
项目摘要
Toxins, pathogenic infection (viral and bacterial), and physical injury to the liver results in a loss of hepatic tissue, triggering a regenerative response to restore liver cell mass. Dysregulation in the repair process can lead to liver failure or liver cancer. The aryl hydrocarbon
receptor (AhR) is a ligand-activated transcription factor functionally identified with proliferative processes. Prolonged AhR signaling such as occurs following exposure to the ligand 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD), induces a range of toxic or adaptive endpoints including a failure of liver regeneration following tissue injury. Our long-term goal is to understand mechanistically how the AhR contributes to liver homeostasis by regulating cell proliferation, and thereby identify the molecular basis for TCDD-induced disruption of normal biological processes. The central hypothesis in this application states that the AhR induces paraoxonase 1 (PON1) gene expression in response to
oxidized low-density lipoproteins (oxLDL) generated during periods of liver regeneration. The hypothesis is based on several observations. First, a report that PON1-an enzyme found in high-density
lipoproteins responsible for inhibiting oxLDL production-is an AhR target gene. Second, the recently published finding that shear-stress induced production of oxLDL can induce AhR activation. Third, that hemodynamic changes triggered by liver injury lead to formation of oxLDL. Moreover, based on our preliminary evidence we propose that PON1 expression uses a unique AhR protein complex binding to a novel non-consensus xenobiotic response element (NC-XRE). The studies described in this proposal
will establish that oxLDL- induced PON1 expression is a NC-XRE-mediated AhR-dependent process during liver regeneration, in which PON1 expression functions primarily to control AhR activity by regulating oxLDL formation. Given PON1's implicated role in protecting against cardiovascular disease,
and now suspected role in liver homeostasis, its regulation by the AhR directly links environmental exposure concerns to significant and pervasive human health problems. Therefore, a mechanistic understanding of these processes is essential.)
肝脏的毒素、病原体感染(病毒和细菌)和物理损伤会导致肝组织损失,从而引发再生反应以恢复肝细胞质量。修复过程中的失调可能导致肝衰竭或肝癌。芳基烃
受体(AhR)是一种配体激活的转录因子,其功能与增殖过程有关。长时间的 AhR 信号传导,例如暴露于配体 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 后发生的延长,会诱导一系列毒性或适应性终点,包括组织损伤后肝脏再生失败。我们的长期目标是从机制上了解 AhR 如何通过调节细胞增殖来促进肝脏稳态,从而确定 TCDD 诱导的正常生物过程破坏的分子基础。本申请的中心假设指出,AhR 会诱导对氧磷酶 1 (PON1) 基因表达以响应
肝脏再生期间产生的氧化低密度脂蛋白(oxLDL)。该假设基于多项观察。首先,有报道称PON1-一种在高密度中发现的酶
负责抑制 oxLDL 产生的脂蛋白是 AhR 靶基因。其次,最近发表的研究结果表明,剪切应力诱导产生 oxLDL 可以诱导 AhR 激活。第三,肝损伤引发的血流动力学变化导致oxLDL的形成。此外,根据我们的初步证据,我们提出 PON1 表达使用独特的 AhR 蛋白复合物与新型非共有外源性反应元件 (NC-XRE) 结合。本提案中描述的研究
将确定 oxLDL 诱导的 PON1 表达是肝再生过程中 NC-XRE 介导的 AhR 依赖性过程,其中 PON1 表达主要通过调节 oxLDL 形成来控制 AhR 活性。鉴于 PON1 在预防心血管疾病方面的重要作用,
现在怀疑它在肝脏稳态中的作用,它由 AhR 的调节直接将环境暴露问题与重大而普遍的人类健康问题联系起来。因此,对这些过程的机械理解至关重要。)
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Cornelis Johan Elferink其他文献
Cornelis Johan Elferink的其他文献
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{{ truncateString('Cornelis Johan Elferink', 18)}}的其他基金
Hepatic Aryl Hydrocarbon Receptor Regulation of Obesity: Mechanisms of Action
肝芳基烃受体对肥胖的调节:作用机制
- 批准号:
10701901 - 财政年份:2022
- 资助金额:
$ 32.74万 - 项目类别:
Gulf Coast Center for Precision Environmental Health
墨西哥湾沿岸精准环境健康中心
- 批准号:
10647883 - 财政年份:2019
- 资助金额:
$ 32.74万 - 项目类别:
Administrative Supplement for Gulf Coast Center for Precision Environmental Health
墨西哥湾沿岸精准环境健康中心行政补充
- 批准号:
10436634 - 财政年份:2019
- 资助金额:
$ 32.74万 - 项目类别:
Gulf Coast Center for Precision Environmental Health
墨西哥湾沿岸精准环境健康中心
- 批准号:
10390320 - 财政年份:2019
- 资助金额:
$ 32.74万 - 项目类别:
Aryl Hydrocarbon Receptor-Mediated Epigenetic Processes
芳基烃受体介导的表观遗传过程
- 批准号:
9124375 - 财政年份:2016
- 资助金额:
$ 32.74万 - 项目类别:
A Novel Paradigm for Aryl Hydrocarbon Receptor Signaling
芳基烃受体信号传导的新范例
- 批准号:
8896257 - 财政年份:2015
- 资助金额:
$ 32.74万 - 项目类别:
Gulf Coast Health Alliance: health Risks related to the Macondo Spill (GC-HARMS)
墨西哥湾沿岸健康联盟:与马孔多泄漏事件相关的健康风险 (GC-HARMS)
- 批准号:
8469037 - 财政年份:2011
- 资助金额:
$ 32.74万 - 项目类别:
Gulf Coast Health Alliance: health Risks related to the Macondo Spill (GC-HARMS)
墨西哥湾沿岸健康联盟:与马孔多泄漏事件相关的健康风险 (GC-HARMS)
- 批准号:
8727814 - 财政年份:2011
- 资助金额:
$ 32.74万 - 项目类别:
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