Thioredoxin Inhibitory Protein in Chronic Liver Disease
慢性肝病中的硫氧还蛋白抑制蛋白
基本信息
- 批准号:8300946
- 负责人:
- 金额:$ 15.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-01 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcetaldehydeAftercareAntioxidantsApoptosisArachidonic AcidsBiochemistryBiological ProcessCancerousCause of DeathCell LineCell ProliferationCellsCellular biologyChronicChronic HepatitisCirrhosisClinicalCpG dinucleotideData AnalysesDevelopmentDiseaseDoctor of MedicineEnvironmentEpigenetic ProcessEthanolFellowshipFibrosisGastroenterologyGene ExpressionGenerationsGenesGenomicsGoalsGrowthHepatic Stellate CellHepatitisHepatocyteHepatologyHumanHypermethylationIn VitroInflammatoryInjuryKnockout MiceKnowledgeLeadLinkLiverLiver FibrosisMalignant Epithelial CellMeasuresMentorsMentorshipMessenger RNAMethylationModelingModificationMolecular BiologyMolecular GeneticsMusOxidative StressPathogenesisPathway interactionsPhysiciansPrimary carcinoma of the liver cellsProcessProtein BindingProteinsReactive Oxygen SpeciesRegulationResearchResearch DesignResearch ProposalsResourcesSamplingScientistSimulateStagingStimulusTestingThioredoxinTissue SampleTissuesTrainingTumor Suppressor Genesbasebisulfitebody systemcareercell growthchronic liver diseaseestablished cell lineexperiencegenetic elementgenome wide association studyhuman tissuein vitro ModelinterestmRNA Expressionoverexpressionpreventprotein activationprotein expressionpublic health relevanceskillsstellate cell
项目摘要
DESCRIPTION (provided by applicant): The primary goal of this proposal is to provide the applicant, James P. Hamilton, M.D., with a significant period of continued mentorship in a strong, supportive scientific environment in order for him to continue developing skills needed to become a fully independent physician-scientist. Dr. Hamilton has undergone superior clinical training in Gastroenterology, including a Fellowship in Advanced Hepatology. Moreover, during his career thus far, Dr. Hamilton has already focused his research interest on the molecular genetic basis of chronic liver disease. To advance his academic career as well as to establish his independence, further training is required in biochemistry, molecular biology, scientific study design, and data analysis. The research proposal described herein will investigate the expression and biologic functions of Thioredoxin Inhibitory Protein (TXNIP) in the pathogenesis of chronic liver disease. His hypothesis is that TXNIP activation in chronic hepatitis leads to increased reactive oxygen species (ROS), which in turn lead to liver fibrosis. He further postulates that once cirrhosis has developed, loss of TXNIP expression, due in part to hypermethylation, results in abnormal hepatocyte growth and proliferation. The proposed project will apply the considerable expertise and resources of the mentor's hepatic fibrosis research with the knowledge and experience of other key collaborators at Johns Hopkins. Specifically, Aim 1 of the current proposal will examine TXNIP expression at the mRNA and protein levels in normal, inflamed, cirrhotic and cancerous liver tissues, as well as in hepatocyte and hepatic stellate cell lines. Aim 2 will scrutinize the biological functions of TXNIP in chronic liver disease in vitro. TXNIP-induced generation of ROS and activation of pro-fibrotic pathways will be examined. Furthermore, effects of TXNIP on cell growth, proliferation, and apoptosis will be determined. Aim 3 will investigate the regulation of TXNIP by methylation. This mechanism will be evaluated directly, using bisulfite sequencing and methylation-specific PCR, as well as indirectly, using demethylating agents to reverse transcriptional silencing.
PUBLIC HEALTH RELEVANCE: Chronic liver disease is a leading cause of death, and the way in which liver injury develops is not fully understood. We will investigate Thioredoxin Inhibitory Protein (TXNIP) in chronic liver disease to determine how this gene may cause increased liver injury. Our results may have profound relevance to developing treatments to lessen or prevent chronic liver injury.
描述(由申请人提供):本提案的主要目标是为申请人James P.汉密尔顿,医学博士,在一个强大的,支持性的科学环境中继续指导的重要时期,以便他继续发展成为一名完全独立的医生科学家所需的技能。汉密尔顿博士接受过胃肠病学的上级临床培训,包括高级肝病学奖学金。此外,在迄今为止的职业生涯中,汉密尔顿博士已经将他的研究兴趣集中在慢性肝病的分子遗传基础上。为了促进他的学术生涯,以及建立他的独立性,进一步的培训,需要在生物化学,分子生物学,科学研究设计和数据分析。本研究拟探讨硫氧还蛋白抑制蛋白(TXNIP)在慢性肝病发病机制中的表达及其生物学功能。他的假设是,TXNIP在慢性肝炎中的激活导致活性氧(ROS)增加,进而导致肝纤维化。他进一步假设,一旦肝硬化发展,TXNIP表达的丧失,部分由于超甲基化,导致异常的肝细胞生长和增殖。拟议的项目将应用导师的肝纤维化研究的大量专业知识和资源,以及约翰霍普金斯其他主要合作者的知识和经验。具体地,本发明的目的1将在正常、发炎、炎性和癌性肝组织以及肝细胞和肝星状细胞系中在mRNA和蛋白质水平上检查TXNIP表达。目的2探讨TXNIP在慢性肝病中的体外生物学作用。将检查TXNIP诱导的ROS产生和促纤维化途径的激活。此外,将确定TXNIP对细胞生长、增殖和凋亡的影响。目的3探讨TXNIP甲基化的调控机制。该机制将使用亚硫酸氢盐测序和甲基化特异性PCR直接评估,以及使用去甲基化剂逆转转录沉默间接评估。
公共卫生相关性:慢性肝病是导致死亡的主要原因,肝损伤的发展方式尚未完全了解。我们将研究慢性肝病中的硫氧还蛋白抑制蛋白(TXNIP),以确定该基因如何导致肝损伤增加。我们的研究结果可能对开发减轻或预防慢性肝损伤的治疗方法具有深远的意义。
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)
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JAMES P HAMILTON其他文献
JAMES P HAMILTON的其他文献
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{{ truncateString('JAMES P HAMILTON', 18)}}的其他基金
Thioredoxin Inhibitory Protein in Chronic Liver Disease
慢性肝病中的硫氧还蛋白抑制蛋白
- 批准号:
7894038 - 财政年份:2010
- 资助金额:
$ 15.58万 - 项目类别:
Thioredoxin Inhibitory Protein in Chronic Liver Disease
慢性肝病中的硫氧还蛋白抑制蛋白
- 批准号:
8049148 - 财政年份:2010
- 资助金额:
$ 15.58万 - 项目类别:
Thioredoxin Inhibitory Protein in Chronic Liver Disease
慢性肝病中的硫氧还蛋白抑制蛋白
- 批准号:
8470633 - 财政年份:2010
- 资助金额:
$ 15.58万 - 项目类别:
Thioredoxin Inhibitory Protein in Chronic Liver Disease
慢性肝病中的硫氧还蛋白抑制蛋白
- 批准号:
8672629 - 财政年份:2010
- 资助金额:
$ 15.58万 - 项目类别:
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