DIAL
DIAL
批准号:
7951423
负责人:
Victor R Gordeuk
金额:
$1.74万
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
项目状态:
已结题
起止时间:
2009-03-01 至 2010-02-28
关键词:
Aconitate HydrataseAfricanAfrican AmericanAlcohol consumptionAlcoholic Liver DiseasesAlcoholsAnimal ModelApoproteinsBindingCell Culture TechniquesCellsClinical ResearchComputer Retrieval of Information on Scientific Projects DatabaseDevelopmentDietary IronElementsEnvironmentEnzymesFerritinFunctional disorderFundingGene ExpressionGrantHeme IronHepaticIn TransferrinInstitutionIronKupffer CellsLiverLiver diseasesNF-kappa BPathogenesisPhysiologicalRNARepressionResearchResearch PersonnelResourcesSourceTestingTranscriptTransferrin ReceptorUnited States National Institutes of HealthUniversitiesbasedesigniron metabolismmacrophagestem
中文摘要
这个子项目是许多研究子项目中利用
资源由NIH/NCRR资助的中心拨款提供。子项目和
调查员(PI)可能从NIH的另一个来源获得了主要资金,
并因此可以在其他清晰的条目中表示。列出的机构是
该中心不一定是调查人员的机构。
这项拟议的研究旨在确定饮食中铁和铁储存的增加是否有助于非裔美国人胆汁性肝病的发展。我们的初步研究表明,在非洲人和非裔美国人中,高膳食铁导致肝脏铁储存增加,而在饮酒的非洲人中,肝脏铁储存增加与肝脏功能障碍有关。我们推测,酒精诱导的肝细胞和Kupffer细胞的氧化环境导致细胞胞浆乌头酸酶/irp 1的铁毛簇的分解,并将该酶转化为与铁代谢转录本中的RNA茎环元件结合的载脂蛋白。Irp1的这种非生理性的IRE结合活性的增加反过来导致铁蛋白合成的异常抑制和转铁蛋白受体合成的异常增加以及潜在的毒性胞浆活性铁浓度的增加。基于我们的细胞培养和动物模型研究,我们进一步推测,库普弗细胞中非血红素铁含量的增加启动了这些细胞的核因子-kB激活和促炎基因的表达,从而参与了非裔美国人酒精性肝病的发病机制。我们的目标是验证两个中心假设:高饮食铁有助于酒精诱导的细胞铁负荷异常的倾向,以及在酒精性肝病的背景下,肝脏铁增加导致肝脏损害。
英文摘要
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source,
and thus could be represented in other CRISP entries. The institution listed is
for the Center, which is not necessarily the institution for the investigator.
The proposed research is designed to determine if increased dietary iron and iron stores contribute to the development of alcholic liver disease in African Americans. Our preliminary studies indicate that high dietary iron leads to increased hepatic iron stores in both Africans and African Americans, and that incrreased hepatic iron stores are associated with hepatic dysfunction in Africans who consume alcohol. We postulate that the oxidative environment induced by alcohol in heptocytes and Kupffer cell (hepatic macrophages) leads to diassembly of the ironfur cluster of cytocolic aconitase/IRP 1 and conversion of this enzyme to an apoprotein that binds to RNA stem loops (iron repsonisve elements-IREs) in iron metabolism transcripts. This non-physiologic increase in IRE-binding activity of IRP1 in turn leads to abnormal repression of ferritin synthesis and abnormal increases in transferrin receptor synthesis and potentially toxic cytosolic labile iron concentrations. Based on our cell culture and animal model studies, we further postulate that increased non-heme iron content in Kupffer cells primes these cell for NF-kB activation and proinflammatory gene expression and thereby contributes to the pathogenesis of alcoholic liver disease in African Americans. We aim to test two central hypotheses: i) high dietary iron contributes to an alcohol induced tendency for abnormal iron-loading of cells, and ii) increased hepatic iron contrributes to liver damage in the setting of alcoholic liver disease.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Improving Sickle cell care in Adolescents & Adults in Chicago (ISAAC)
-
批准号:9482318
-
项目类别:
-
资助金额:$4.89万
-
财政年份:2017
-
负责人:Victor R Gordeuk
-
依托单位:
Improving Sickle cell care in Adolescents & Adults in Chicago (ISAAC)
-
批准号:9928658
-
项目类别:
-
资助金额:$10.34万
-
财政年份:2016
-
负责人:Victor R Gordeuk
-
依托单位:
Improving Sickle cell care in Adolescents & Adults in Chicago (ISAAC)
-
批准号:9928286
-
项目类别:
-
资助金额:$8.31万
-
财政年份:2016
-
负责人:Victor R Gordeuk
-
依托单位:
Improving Sickle cell care in Adolescents & Adults in Chicago (ISAAC)
-
批准号:9180588
-
项目类别:
-
资助金额:$70.67万
-
财政年份:2016
-
负责人:Victor R Gordeuk
-
依托单位:
Improving Sickle cell care in Adolescents & Adults in Chicago (ISAAC)
-
批准号:9326337
-
项目类别:
-
资助金额:$64.47万
-
财政年份:2016
-
负责人:Victor R Gordeuk
-
依托单位:
Improving Sickle cell care in Adolescents & Adults in Chicago (ISAAC)
-
批准号:10160619
-
项目类别:
-
资助金额:$8.44万
-
财政年份:2016
-
负责人:Victor R Gordeuk
-
依托单位:
Improving Sickle cell care in Adolescents & Adults in Chicago (ISAAC)
-
批准号:10197197
-
项目类别:
-
资助金额:$58.86万
-
财政年份:2016
-
负责人:Victor R Gordeuk
-
依托单位:
Improving Sickle cell care in Adolescents & Adults in Chicago (ISAAC)
-
批准号:10465381
-
项目类别:
-
资助金额:$2.61万
-
财政年份:2016
-
负责人:Victor R Gordeuk
-
依托单位:
Sickle Cell Scholar Component
-
批准号:7988366
-
项目类别:
-
资助金额:$1.27万
-
财政年份:2009
-
负责人:Victor R Gordeuk
-
依托单位:
Washington Area Basic and Translational Research Program
-
批准号:7819148
-
项目类别:
-
资助金额:$1.61万
-
财政年份:2009
-
负责人:Victor R Gordeuk
-
依托单位:
CLINICAL TRIAL: BIOMARIN
-
批准号:7951444
-
项目类别:
-
资助金额:$2.61万
-
财政年份:2009
-
负责人:Victor R Gordeuk
-
依托单位:
CLINICAL TRIAL: VASCO
-
批准号:7951452
-
项目类别:
-
资助金额:$1.84万
-
财政年份:2009
-
负责人:Victor R Gordeuk
-
依托单位:
Administrative Core
-
批准号:7821240
-
项目类别:
-
资助金额:$22.33万
-
财政年份:2009
-
负责人:Victor R Gordeuk
-
依托单位:
Administrative Core
-
批准号:7988368
-
项目类别:
-
资助金额:$1.27万
-
财政年份:2009
-
负责人:Victor R Gordeuk
-
依托单位:
PUSH
-
批准号:7951426
-
项目类别:
-
资助金额:$11.31万
-
财政年份:2009
-
负责人:Victor R Gordeuk
-
依托单位:
CLINICAL TRIAL: WALK PHASST
-
批准号:7951450
-
项目类别:
-
资助金额:$10.05万
-
财政年份:2009
-
负责人:Victor R Gordeuk
-
依托单位:
Sickle Cell Scholar Component
-
批准号:7821239
-
项目类别:
-
资助金额:$22.33万
-
财政年份:2009
-
负责人:Victor R Gordeuk
-
依托单位:
Washington Area Basic and Translational Research Program
-
批准号:7890732
-
项目类别:
-
资助金额:$3.8万
-
财政年份:2009
-
负责人:Victor R Gordeuk
-
依托单位:
Washington Area Comprehensive Sickle Cell Center
-
批准号:8135101
-
项目类别:
-
资助金额:$3.8万
-
财政年份:2008
-
负责人:Victor R Gordeuk
-
依托单位:
Washington Area Comprehensive Sickle Cell Center
-
批准号:7640492
-
项目类别:
-
资助金额:$69.98万
-
财政年份:2008
-
负责人:Victor R Gordeuk
-
依托单位:
海外基金