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:7817754
- 负责人:
- 金额:$ 37.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-20 至 2012-09-19
- 项目状态:已结题
- 来源:
- 关键词:AgonistAnatomyAntiatherogenicAryl Hydrocarbon ReceptorBindingBiological ProcessCYP1A1 geneCardiovascular DiseasesCationsCell ProliferationComplexConsensusDataDependenceDioxinsEnvironmental ExposureEnvironmental PollutantsEnzymesExposure toFailureFeedbackFundingGene ExpressionGene TargetingGenesGoalsHealthHepatic MassHepatic TissueHepatocyteHigh Density LipoproteinsHomeostasisHumanInjuryInjury to LiverInsecticidesLeadLigandsLinkLiverLiver FailureLiver RegenerationLow Density Lipoprotein oxidationLow-Density LipoproteinsMalignant neoplasm of liverMediatingMetabolicMetabolismMolecularMusParaoxonase 1ParentsPartial HepatectomyPlasminogen Activator Inhibitor 1PlayProcessProductionProteinsPublishingRattusReceptor ActivationReceptor SignalingRecoveryRegulationRelative (related person)ReportingResearchResponse ElementsRoleSignal PathwaySignal TransductionTetrachlorodibenzodioxinTissuesToxic effectToxinUnited States National Institutes of HealthVirus DiseasesXenobioticsactivating transcription factoraryl hydrocarbon receptor ligandaryldialkylphosphataseautocrinebasedesignextracellularhemodynamicshepatoma cellhuman CDK2 proteinin vivonoveloxidized low density lipoproteinparent grantprotein complexpublic health relevancereceptorregenerativerepairedresponsesensorshear stresstranscription factor
项目摘要
DESCRIPTION (provided by applicant): This is an application in response to the NIH Notice Number NOT-OD-09-058, entitled "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Application." 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.)
PUBLIC HEALTH RELEVANCE: Injury to the liver resulting in a loss of tissue triggers a repair process designed to restore liver mass, where inappropriate repair can lead to liver failure or liver cancer. The aryl hydrocarbon receptor (AhR) is a protein that plays a central role in liver repair in addition to being a sensor for environmental pollutants. Therefore, the AhR directly links environmental exposure concerns to significant and pervasive human health problems.)
描述(由申请人提供):这是一项针对NIH通知编号NOT-OD-09-058的申请,标题为“NIH宣布恢复法资金可用于竞争性修订申请”。毒素、病原性感染(病毒和细菌)和对肝脏的物理损伤会导致肝组织的损失,触发再生反应来恢复肝细胞质量。修复过程中的失调可能会导致肝功能衰竭或肝癌。芳香烃受体(AhR)是一种配体激活的转录因子,功能上与增殖过程有关。2,3,7,8-四氯二苯并-对-二恶英(TCDD)引起的AhR信号的延长会导致一系列的毒性或适应性终点,包括组织损伤后肝再生的失败。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动态平衡,从而确定TCDD诱导的正常生物学过程中断的分子基础。本应用的中心假设是AhR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型低密度脂蛋白(OxLDL)。这一假设是基于几个观察结果。首先,有报道称,PON1是AhR的目标基因,PON1是高密度脂蛋白中发现的一种酶,负责抑制oxLDL的产生。第二,最近发表的研究发现,切应力诱导oxLDL的产生可以诱导AhR的激活。第三,肝损伤引发的血流动力学改变导致oxLDL的形成。此外,根据我们的初步证据,我们认为PON1的表达使用了一个独特的AhR蛋白复合体与一个新的非共识异种反应元件(NC-XRE)结合。这项研究将证明oxLDL诱导的PON1表达是肝脏再生过程中NC-XRE介导的AhR依赖的过程,其中PON1的表达主要通过调节oxLDL的形成来控制AhR的活性。鉴于PON1的S在预防心血管疾病中的牵连作用,以及现在被怀疑在肝脏动态平衡中的作用,其由AhR的调节直接将环境暴露问题与重大和普遍的人类健康问题联系在一起。因此,对这些过程的机械性理解至关重要。)
公共卫生相关性:肝脏损伤导致组织丢失,触发旨在恢复肝脏质量的修复过程,其中不适当的修复可能导致肝功能衰竭或肝癌。芳香烃受体(AhR)是一种蛋白质,除了作为环境污染物的传感器外,它还在肝脏修复中发挥核心作用。因此,《环境影响评估报告》直接将环境暴露问题与重大和普遍的人类健康问题联系起来。)
项目成果
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Cornelis Johan Elferink其他文献
Cornelis Johan Elferink的其他文献
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10436634 - 财政年份:2019
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