The role of oxidative stress in alcohol-induced osteopenia
氧化应激在酒精引起的骨质减少中的作用
基本信息
- 批准号:9126707
- 负责人:
- 金额:$ 49.58万
- 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:2016-05-15 至 2021-04-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAcetylcysteineAdipocytesAffectAgeAgingAlcohol abuseAlcohol consumptionAlcoholsAlkaline PhosphataseAntioxidantsApoptosisApplications GrantsAreaBone DevelopmentBone Formation InhibitionBone GrowthBone MarrowBone Marrow CellsBone ResorptionBone remodelingCell Culture TechniquesCell LineCellsCharacteristicsColony-forming unitsComplement Factor BComplexConsumptionDataDaughterDevelopmentDietDiseaseElderlyEnzymesEthanolEthanol MetabolismEthanol toxicityFamilyFamily memberFemaleFibroblastsFundingHeavy DrinkingHumanHydrogen PeroxideImpairmentIn VitroInflammationInjuryInvestigationKnock-outLigandsLinkLiquid substanceMediatingMenopauseMesenchymal Stem CellsMessenger RNAMetabolismMitochondriaModelingMolecularMorphologyMusNADHNADPH OxidaseNIH Program AnnouncementsNational Institute on Alcohol Abuse and AlcoholismNuclearObesityOsteoblastsOsteocalcinOsteoclastsOsteocytesOsteogenesisOsteopeniaOsteoporosisOxidative StressPathway interactionsPeroxisome Proliferator-Activated ReceptorsProductionRattusReactive Oxygen SpeciesRegulationResearchRiskRisk FactorsRoleSerumSignal TransductionSignaling MoleculeSkeletal MuscleSourceStem cellsSurfaceT-LymphocyteTNF geneTNFSF11 geneTP53 geneTestingTissuesTocopherolsToxic effectTransgenic MiceVitamin EWild Type MouseWomanadipocyte differentiationage relatedalcohol effectbinge drinkingbody systembonebone cellbone lossbone massbone turnovercatalasecytokinedietary antioxidantdiphenyleneiodoniumdrinkingemerging adultfeedingin vivoinhibitor/antagonistinjury and repairinsightknock-downmembermenolder womenosteoclastogenesisosteogenicpreventprogenitorpublic health relevancereceptorresponseself-renewalsenescencestem cell differentiationtranscription factoryoung woman
项目摘要
DESCRIPTION (provided by applicant): Although it is well known that women are more susceptible to the toxic effects of ethanol (EtOH) than men, much less is known about the molecular mechanisms underlying alcohol toxicity in women especially as relates to bone. Alcohol abuse during early adulthood results in impaired bone growth and in the U.S.A. approximately 20% of women age 18-30 (4.4 million) binge drink. A resulting reduction in peak bone mass would predispose women to osteoporosis in later life. The molecular mechanisms underlying the toxic effects of EtOH on bone remain poorly understood. EtOH inhibits bone formation. Bone loss in female rats and mice fed EtOH is blocked by dietary antioxidants including N-acetylcysteine and vitamin E and by DPI an inhibitor of NADPH oxidase (NOX) enzymes. However, effects of EtOH to inhibit osteoblastogenesis and stimulate bone marrow adiposity were not blocked in p47phox -/- mice lacking active NOX1/2. We hypothesize that another source of reactive oxygen species (ROS) mediates the effects of EtOH on bone formation. Ex-vivo bone marrow cultures from NOX 4 -/- mice will be utilized to test the hypothesis that NOX4 mediates the effects EtOH-induced inhibition of mesenchymal stem cell self-renewal and differentiation into osteoblasts or adipocytes. A mouse liquid diet model will be used to test this hypothesis in vivo in mice with cell specific ablation of NOX4 in osteoblast precursors (Prx-1-Cre-lox mice). Alternatively, the role of mitochondrial derived ROS in EtOH inhibition of bone formation will be tested using the mitochondrial ROS inhibitor mitoTEMPO. At higher concentrations characteristic of binge drinking, EtOH can also increase bone resorption via induction of RANKL, a member of the TNF family expressed primarily in osteocytes, which signals through the receptor RANK to stimulate osteoclastogenesis. The role of NOX derived ROS in EtOH-induced RANKL production from osteocytes and other effects of EtOH on osteocyte function and cortical bone morphology will be determined in vivo in mice lacking NOX4 or with inactive NOX1/2 in osteocytes (NOX4 and rac-1 Dmp-1 Cere-lox mice) fed EtOH via liquid diet and in an EtOH binge drinking model. In addition, the role of excess NADH produced during EtOH metabolism in NOX activation will be tested in bone cells in vitro.
描述(申请人提供):尽管众所周知,女性比男性更容易受到乙醇(Etoh)的毒性影响,但人们对女性酒精中毒的分子机制知之甚少,尤其是与骨骼有关的机制。成年早期酗酒会导致骨骼生长受损,在美国,18-30岁的女性中约有20%(440万)酗酒。由此导致的峰值骨量的减少将使女性在晚年更容易患上骨质疏松症。乙醇对骨骼的毒性作用的分子机制仍然知之甚少。乙醇抑制骨形成。饮食中的抗氧化剂,包括N-乙酰半胱氨酸和维生素E,以及NADPH氧化酶(NOX)的抑制剂DPI,可以阻止喂食乙醇的雌性大鼠和小鼠的骨丢失。然而,在缺乏活性NOX1/2的p47Phox-/-小鼠中,乙醇抑制成骨细胞生成和刺激骨髓肥大的作用并未被阻断。我们假设,乙醇对骨形成的影响可能是由另一种来源的活性氧(ROS)介导的。NOX4-/-小鼠的体外骨髓培养将被用来检验NOX4介导乙醇诱导的抑制间充质干细胞自我更新和向成骨细胞或脂肪细胞分化的作用的假说。小鼠液体饮食模型将在体内用成骨细胞前体细胞特异性消融NOX4的小鼠(PRX-1-CRE-LOX小鼠)来验证这一假说。或者,将使用线粒体ROS抑制剂MitoTEMPO来测试线粒体衍生的ROS在乙醇抑制骨形成中的作用。在酗酒所特有的较高浓度下,乙醇还可以通过诱导RANKL增加骨吸收,RANKL是主要在骨细胞中表达的肿瘤坏死因子家族成员,它通过受体RANK发出信号来刺激破骨细胞的形成。NOX衍生的ROS在Etoh诱导的骨细胞RANKL产生中的作用以及Etoh对骨细胞功能和皮质骨形态的其他影响将在体内通过液体饮食和Etoh酗酒模型确定缺乏NOX4或骨细胞中NOX1/2不活跃的小鼠(NOX4和Rac-1DMP-1 Cere-lox小鼠)。此外,乙醇代谢过程中产生的过量NADH在NOX激活中的作用将在体外骨细胞中进行测试。
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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Martin J J Ronis其他文献
Martin J J Ronis的其他文献
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{{ truncateString('Martin J J Ronis', 18)}}的其他基金
The role of oxidative stress in alcohol-induced osteopenia
氧化应激在酒精引起的骨质减少中的作用
- 批准号:
10406154 - 财政年份:2021
- 资助金额:
$ 49.58万 - 项目类别:
The role of oxidative stress in alcohol-induced osteopenia
氧化应激在酒精引起的骨质减少中的作用
- 批准号:
10608146 - 财政年份:2021
- 资助金额:
$ 49.58万 - 项目类别:
The role of oxidative stress in alcohol-induced osteopenia
氧化应激在酒精引起的骨质减少中的作用
- 批准号:
9919470 - 财政年份:2016
- 资助金额:
$ 49.58万 - 项目类别:
The role of oxidative stress in alcohol-induced osteopenia
氧化应激在酒精引起的骨质减少中的作用
- 批准号:
9344518 - 财政年份:2016
- 资助金额:
$ 49.58万 - 项目类别:
Prevention of EtOH-induced promotion of hepatocarcinogenesis by genistein/soy
金雀异黄素/大豆预防乙醇诱导的肝癌发生
- 批准号:
8354189 - 财政年份:2012
- 资助金额:
$ 49.58万 - 项目类别:
Prevention of EtOH-induced promotion of hepatocarcinogenesis by genistein/soy
金雀异黄素/大豆预防乙醇诱导的肝癌发生
- 批准号:
8547039 - 财政年份:2012
- 资助金额:
$ 49.58万 - 项目类别:
Alcohol-Induced Bone Resorption: The Role of Oxidative Stress
酒精引起的骨吸收:氧化应激的作用
- 批准号:
8497553 - 财政年份:2009
- 资助金额:
$ 49.58万 - 项目类别:
Alcohol-Induced Bone Resorption: The Role of Oxidative Stress
酒精引起的骨吸收:氧化应激的作用
- 批准号:
8299084 - 财政年份:2009
- 资助金额:
$ 49.58万 - 项目类别:
Alcohol-Induced Bone Resorption: The Role of Oxidative Stress
酒精引起的骨吸收:氧化应激的作用
- 批准号:
7890356 - 财政年份:2009
- 资助金额:
$ 49.58万 - 项目类别:
Alcohol-Induced Bone Resorption: The Role of Oxidative Stress
酒精引起的骨吸收:氧化应激的作用
- 批准号:
8100109 - 财政年份:2009
- 资助金额:
$ 49.58万 - 项目类别:
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